Anti-bacterial compounds based on amino-gold phosphine complexes

ABSTRACT

A compound of formula (I) for use in the prevention or treatment of a bacterial infection wherein: P X  is selected from the group consisting of (P1), (P2) and (P3).

The present invention relates to gold(I)-phosphine compounds, and their use as inhibitors of growth of Gram-positive and/or Gram-negative bacteria. The present invention also relates to using such compounds for the prevention and/or treatment of bacterial infection.

The global rise of bacteria and other microorganisms resistant to antibiotics and antimicrobials in general, poses a major threat. Deployment of massive quantities of antimicrobial agents into the human ecosphere during the past 60 years has introduced a powerful selective pressure for the emergence and spread of antimicrobial-resistant bacterial pathogens. The World Health Organization has highlighted antimicrobial resistance (AMR) as an issue of global concern in 2014. AMR is now present in all parts of the world with the incidence of antibiotic resistance (ABR) in bacteria that cause common infections (e.g. pneumonia, bloodstream infections and urinary tract infections) rendering many historically efficacious antibiotics ineffective. Of particular concern are hospital-acquired infections caused by highly resistant bacteria such as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), Escherichia coli, Coagulase-negative staphylococci and Clostridium difficile. Additionally, failure of last resort third-generation cephalosporins for the treatment of gonorrhea has now been reported in 10 countries raising the possibility that gonorrhea may soon become untreatable in the absence of new antibacterial agents.

The biological activity of gold(I) and gold(III) complexes has been studied historically and salts of both have been demonstrated to possess antimicrobial activity against a range of pathogens. Gold(I) complexes have historically been reported as having antibacterial activity against Gram positive organisms. (Glisic, B. D. & Djuran M. I., Dalton Trans., 2014, 43, 5950-5969). For example, Nomiya (Nomiya, K., et al., J. Inorganic Biochem., 2003, 95, 208-220) discloses triphenyl phosphine compounds with a variety of ligands with antibacterial activity against Gram positive organisms, and Aguinagalde, L., et al., J. Antimicrob. Chemother., 2015, 70(9), 2608-2617 discloses six triethyl phosphine compounds with antibacterial activity against Gram positive organisms.

Gold(I) is a soft Lewis acid and preferentially complexes with soft donor atoms such as sulfur, selenium and phosphorous. Examples of such complexes used clinically include gold thiomalate, aurothioglucose and auranofin:

Auranofin, a second generation orally bioavailable gold(I) based treatment for rheumatoid arthritis (RA), has been identified as inhibiting the in vitro growth of S. aureus (Oxford strain) with an MIC of 0.6-0.9 μg/mL and V. cholerae with an MIC of 2.5 μg/mL. These observations reinforce multiple literature reports of the antimicrobial activity of auranofin and other gold(I) compounds against a range of bacterial pathogens (Madeira, J M., Inflammopharmacology, 2012, 20, 297-306; Jackson-Rosario, S, J. Biol. Inorg. Chem., 2009, 14(4), 507-519; Novelli, F., Farmaco, 1999, 54, 232-236; Shaw, O F, Chem Rev., 1999, 99(9), 2589-2600; Rhodes, M D, J. Inorg. Biochem., 1992, 46, 129-142 and Fricker, S P, Transition Met. Chem., 1996, 21, 377-383). Auranofin has not been shown to have any significant activity against the majority of Gram negative bacteria.

Co-pending applications PCT/GB2015/051551 and PCT/GB2015/051550 describe certain gold(I) phosphine compounds and their use as inhibitors of growth of Gram-positive and/or Gram-negative bacteria.

A first aspect of the present invention provides a compound of formula (I):

for use in the prevention or treatment of a bacterial infection wherein: P^(X) is selected from the group consisting of (P1), (P2) and (P3);

wherein R^(P1) and R^(P2) are each independently selected from

-   -   methyl, ethyl, isopropyl and phenyl;         R^(P3) is selected from the group consisting of     -   methyl and ethyl,     -   isopropyl, t-butyl,     -   cyclopentyl,     -   phenyl,     -   4-membered or 5-membered heterocycloalkyl group linked to         phosphorus via a carbon atom in the ring, including a single         heteroatom independently selected from NR^(Z), O and S,     -   —CF₃, —CH₂CF₃, —CH₂CF₂H, —CH₂CH₂OR^(PB),     -   —CH₂Q and —(CH₂)₂Q;         wherein Q is a C₅₋₆ heteroaryl group, optionally substituted         with one or more groups R^(PA);         R^(P4) is selected from methyl and ethyl;         m is an integer selected from 1, 2 or 3;         R^(M) is one or more optional substituents on the ring         independently selected from     -   R^(PC) when attached to a carbon atom adjacent the phosphorus         atom, or     -   —OH, —OC₁₋₃alkyl and R^(PC), when attached to other ring         carbons;         -L^(B)- is methylene, ethylene or is absent;         when -L^(B)- is present, R^(P4) is absent and R¹ is selected         from N, CH and CR^(PC);         when -L^(B)- is absent, R¹ is selected from the group consisting         of     -   O,     -   NR^(Z),     -   SO₂,     -   CH₂, CHF, CF₂ and CHR^(PC);         wherein R^(Z) is selected from the group consisting of     -   H, C₁₋₃alkyl, COC₁₋₃alkyl and SO₂C₁₋₃alkyl;         R⁵ and R⁸ are each independently selected from H and R^(PC);         R⁶ and R⁷ are each independently selected from H and R^(PC);         wherein R^(PC) is selected from the group consisting of     -   C₁₋₃alkyl, optionally substituted with one or more groups         R^(PD);         wherein R^(PA) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   —F, —Cl, —Br, —CN     -   —OH, —OR^(PE),     -   —CF₃, —CF₂H,     -   —COR^(PE),     -   —CH₂OH, —CH₂OR^(PE),     -   —COOH, —COOR^(PE), —CONH₂, —CONHR^(PE), —CONR^(PE) ₂,     -   —OCOR^(PE), —OCONH₂, —OCONHR^(PE), —OCONR^(PE) ₂,     -   —NH₂, —NHR^(PE), —NR^(PE) ₂,     -   —SO₂NH₂, —SO₂NHR^(PE) ₂, —SO₂NR^(PE) ₂,     -   —SO₂R^(PE),     -   —NHCOH, —NHCOR^(PE), —NR^(PE)COH and —NR^(PE)COR^(PE);         and R^(PB) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(A)T,     -   C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or         C₅₋₆heterocycloalkenyl optionally substituted with one or more         groups R^(AT),     -   phenyl optionally substituted with one or more groups R^(AR),         and     -   C₅₋₆heteroaryl optionally substituted with one or more groups         R^(AR);         R^(PE) is selected from     -   linear or branched C₁₋₄alkyl optionally substituted with one or         more groups R^(PD);         and R^(PD) is selected from the group consisting of     -   F,     -   OH and OC₁₋₃alkyl;         R^(A) is selected from the group consisting of     -   H;     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,         C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl and         C₅₋₆heterocycloalkenyl optionally substituted with one or more         groups R^(AL),     -   C₅₋₆heteroaryl, optionally substituted with one or more groups         R^(A1),     -   C₁₋₃alkyl substituted by phenyl or C₅₋₆heteroaryl, which groups         may optionally substituted with one or more groups R^(A1),         R^(B) is selected from —COR^(A2) and —SO₂R^(A2);         or R^(A) and R^(B) together with the nitrogen atom to which they         are attached form     -   a 5- or 6-membered heteroaryl, heterocycloalkyl or         heterocycloalkenyl group optionally substituted with one or more         groups selected from         -   oxo,         -   ═NH;         -   phenyl optionally substituted with one or more groups             R^(A1),         -   R^(A2), and         -   R^(A1);     -   an 8- to 10-membered heterobicyclyl group optionally substituted         with one or more groups selected from         -   oxo,         -   —NO₂;         -   —C(═O)N(R^(N1))₂, wherein each R^(N1) is independently             selected from R^(N2) and —OR^(N3), wherein R^(N2) and R^(N3)             are each independently selected from linear unsubstituted             C₁₋₆alkyl;         -   phenyl optionally substituted with one or more groups             R^(A1),         -   R^(A2) and         -   R^(A1);             with the proviso that when P^(X) is P(C₂H₅)₃, —NR^(A)R^(B)             is not selected from the groups (X1) or (X6)

wherein R^(A1) is selected from the group consisting of

-   -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   —F, —Cl, —Br, —CN     -   —OH, —OR^(A2),     -   —CF₃, —CF₂H,     -   —COR^(A2),     -   —CH₂OH, —CH₂OR^(A2), —CHR^(A2)OH, CHR^(A2)OR^(A2)     -   —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂,     -   —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂,     -   —NH₂, —NHR^(A2), —NR^(A2) ₂,     -   —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂,     -   —SO₂R^(A2),     -   —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2);         R^(A2) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AT),     -   C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or         C₅₋₆heterocycloalkenyl optionally substituted with one or more         groups R^(AT),     -   phenyl optionally substituted with one or more groups R^(AR),         and     -   C₅₋₁₀heteroaryl optionally substituted with one or more groups         R^(AR);         where N is substituted by 2 R^(A2) groups, the N and the R^(A2)         groups may together form a N-containing C₅₋₆ heterocycloalkyl         group;         R^(AL) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl optionally substituted with one or         more groups R^(AT);     -   —F, —CN     -   —OH, —OR^(A2),     -   —CF₃, —CF₂H,     -   —COR^(A2),     -   —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂,     -   —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂,     -   —NH₂, —NHR^(A2), —NR^(A2) ₂,     -   —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂,     -   —SO₂R^(A2),     -   —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2); and         wherein R^(AR) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   —F, —Cl, —Br, —CN     -   —OH, —OR^(1A1),     -   —CF₃, —CF₂H,     -   —COR^(1A1),     -   —CH₂OH, —CH₂OR^(1A1), —CHR^(1A1)OH, CHR^(1A1)OR^(1A1)     -   —COOH, —COOR^(1A1), —CONH₂, —CONHR^(1A1), —CONR^(1A1) ₂,     -   —OCOR^(1A1), —OCONH₂, —OCONHR^(1A1), —OCONR^(1A1) ₂,     -   —NH₂, —NHR^(1A1), —NR^(1A1) ₂,     -   —SO₂NH₂, —SO₂NHR^(1A1) ₂, —SO₂NR^(1A1) ₂,     -   —SO₂R^(1A1),     -   —NHCOH, —NHCOR^(1A1), —NR^(1A1)COH and —NR^(1A1)COR^(1A1);         R^(AT) is selected from the group consisting of     -   —F, —CN     -   —OH, —OC₁₋₃alkyl,     -   —CF₃, —CF₂H,     -   —COC₁₋₃alkyl,     -   —COOH, —COOC₁₋₃alkyl, —CONH₂, —CONHC₁₋₃alkyl, —CON(C₁₋₃alkyl)₂,     -   —OCOC₁₋₃alkyl, —OCONH₂, —OCONHC₁₋₃alkyl, —OCON(C₁₋₃alkyl)₂,     -   —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)₂,     -   —SO₂NH₂, —SO₂NH(C₁₋₃alkyl)₂, —SO₂N(C₁₋₃alkyl)₂,     -   —SO₂(C₁₋₃alkyl),     -   —NHCOH, —NHCO(C₁₋₃alkyl), —N(C₁₋₃alkyl)COH and         —N(C₁₋₃alkyl)CO(C₁₋₃alkyl);         and pharmaceutically acceptable salts and solvates thereof.

In some embodiments of the first aspect,

R^(P1) and R^(P2) are each independently selected from

-   -   methyl and ethyl;         R^(P3) is selected from the group consisting of     -   methyl and ethyl,     -   4-membered or 5-remembered heterocycloalkyl group linked to         phosphorus via a carbon atom in the ring, including a single         heteroatom independently selected from N, O and S,     -   —CF₃, —CH₂CF₃, —CH₂CF₂H, —CH₂CH₂OR^(PB),     -   —CH₂Q and —(CH₂)₂Q;         R^(A) and R^(B) together with the nitrogen atom to which they         are attached form a 5- or 6-membered heteroaryl,         heterocycloalkyl or heterocycloalkenyl group optionally         substituted with one or more groups selected from     -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1)     -   R^(A2), and     -   R^(A1);         or an 8- to 10-membered heterobicyclyl group optionally         substituted with one or more groups selected from     -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2) and     -   R^(A1).

The first aspect of the invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prevention of a bacterial infection. The first aspect of the invention further provides the treatment of a human or animal patient afflicted with a bacterial infection, comprising administering to said patient an effective amount of a pharmaceutical composition containing a compound of formula (I).

In the first aspect, the bacterial infection prevented and/or treated may be infection by one or more Gram-positive bacteria. The bacterial infection prevented and/or treated may be infection by one or more Gram-negative bacteria. In the first aspect, the bacterial infection prevented and/or treated may be infection by one or more multi-drug resistant bacteria.

The first aspect may also relate to the treatment of fungal infection, e.g. by providing a compound of formula (I) for use in the prevention or treatment of a fungal infection.

Compounds of the present invention may also be used to treat conditions by interaction, e.g. binding to thioredoxin reductase (TrxR), glutathione peroxidase (GSPx), IκB kinase (IKK) complex, cathepsins and type I iodothyronine deiodinase.

In some embodiments of the first aspect, when P^(X) is P(CH₃)₃, —NR^(A)R^(B) is not selected from the group (X15):

A second aspect of the present invention provides a compound of formula (I):

P^(X) is selected from the group consisting of (P1), (P2) and (P3);

wherein R^(P1) and R^(P2) are each independently selected from

-   -   methyl, ethyl, isopropyl and phenyl;         R^(P3) is selected from the group consisting of     -   methyl and ethyl,     -   isopropyl, t-butyl,     -   cyclopentyl,     -   phenyl,     -   4-membered or 5 membered heterocycloalkyl group linked to         phosphorus via a carbon atom in the ring, including a single         heteroatom independently selected from N, O and S,     -   —CF₃, —CH₂CF₃, —CH₂CF₂H, —CH₂CH₂OR^(PB),     -   —CH₂Q and —(CH₂)₂Q;         wherein Q is a C₅₋₆ heteroaryl group, optionally substituted         with one or more groups R^(PA);         R^(P4) is selected from methyl and ethyl;         m is an integer selected from 1, 2 or 3;         R^(M) is one or more optional substituents on the ring         independently selected from     -   R^(PC) when attached to a carbon atom adjacent the phosphorus         atom, or     -   —OH, —OC₁₋₃alkyl and R^(PC), when attached to other ring         carbons;         -L^(B)- is methylene, ethylene or is absent;         when -L^(B)- is present, R^(P4) is absent and R¹ is selected         from N, CH and CR^(PC);         when -L^(B)- is absent, R¹ is selected from the group consisting         of     -   O,     -   NR^(Z),     -   SO₂,     -   CH₂, CHF, CF₂ and CHR^(PC);         wherein R^(Z) is selected from the group consisting of     -   —H, —C₁₋₃alkyl, —COC₁₋₃alkyl and —SO₂C₁₋₃alkyl;         R⁵ and R⁸ are each independently selected from H and R^(PC);         R⁶ and R⁷ are each independently selected from H and R^(PC);         wherein R^(PC) is selected from the group consisting of     -   C₁₋₃alkyl, optionally substituted with one or more groups         R^(PD);         wherein R^(PA) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   —F, —Cl, —Br, —CN     -   —OH, —OR^(PE),     -   —CF₃, —CF₂H,     -   —COR^(PE),     -   —CH₂OH, —CH₂OR^(PE),     -   —COOH, —COOR^(PE), —CONH₂, —CONHR^(PE), —CONR^(PE) ₂,     -   —OCOR^(PE), —OCONH₂, —OCONHR^(PE), —OCONR^(PE) ₂,     -   —NH₂, —NHR^(PE), —NR^(PE) ₂,     -   —SO₂NH₂, —SO₂NHR^(PE) ₂, —SO₂NR^(PE) ₂,     -   —SO₂R^(PE),     -   —NHCOH, —NHCOR^(PE), —NR^(PE)COH and —NR^(PE)COR^(PE);         and R^(PB) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AT),     -   C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or         C₅₋₆heterocycloalkenyl optionally substituted with one or more         groups R^(AT),     -   phenyl optionally substituted with one or more groups R^(AR),         and     -   C₅₋₆heteroaryl optionally substituted with one or more groups         R^(AR);         R^(PE) is selected from     -   linear or branched C₁₋₄alkyl optionally substituted with one or         more groups R^(PD);         and R^(PD) is selected from the group consisting of     -   F,     -   OH and OC₁₋₃alkyl;         R^(A) is selected from the group consisting of     -   H;     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,         C₂₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl and         C₅₋₆heterocycloalkenyl optionally substituted with one or more         groups R^(AL),     -   C₅₋₆heteroaryl, optionally substituted with one or more groups         R^(A1),         C₁₋₃alkyl substituted by phenyl or C₅₋₆heteroaryl, which groups         may optionally substituted with one or more groups R^(A1),         R^(B) is selected from —COR^(A2) and —SO₂R^(A2);         or R^(A) and R^(B) together with the nitrogen atom to which they         are attached form     -   a 5- or 6-membered heteroaryl, heterocycloalkyl or         heterocycloalkenyl group optionally substituted with one or more         groups selected from         -   oxo,         -   ═NH;         -   phenyl optionally substituted with one or more groups             R^(A1),         -   R^(A2) and         -   R^(A1);     -   an 8- to 10-membered heterobicyclyl group optionally substituted         with one or more groups selected from         -   oxo,         -   —NO₂;         -   —C(═O)N(R^(N1))₂, wherein each R^(N1) is independently             selected from R^(N2) and —OR^(N3), wherein R^(N2) and R^(N3)             are each independently selected from linear unsubstituted             C₁₋₆alkyl;         -   phenyl optionally substituted with one or more groups             R^(A1),         -   R^(A2) and         -   R^(A1);             with the proviso that when P^(X) is P(CH₃)₃, —NR^(A)R^(B) is             not selected from any of the groups (X1) to (X5) and (X7);             and with the proviso that when P^(X) is P(C₂H₅)₃,             —NR^(A)R^(B) is not selected from the groups (X1), and (X6)             to (X11)

wherein R^(A1) is selected from the group consisting of

-   -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   —F, —Cl, —Br, —CN     -   —OH, —OR^(A2),     -   —CF₃, —CF₂H,     -   —COR^(A2),     -   —CH₂OH, —CH₂OR^(A2), —CHR^(A2)OH, CHR^(A2)OR^(A2)     -   —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂,     -   —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂,     -   —NH₂, —NHR^(A2), —NR^(A2) ₂,     -   —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂,     -   —SO₂R^(A2),     -   —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2);         R^(A2) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AT),     -   C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or         C₅₋₆heterocycloalkenyl optionally substituted with one or more         groups R^(AT),     -   phenyl optionally substituted with one or more groups R^(AR),         and     -   C₅₋₁₀heteroaryl optionally substituted with one or more groups         R^(AR);         where N is substituted by 2 R^(A2) groups, the N and the R^(A2)         groups may together form a N-containing C₅₋₆ heterocycloalkyl         group;         R^(AL) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl optionally substituted with one or         more groups R^(AT);     -   —F, —CN     -   —OH, —OR^(A2),     -   —CF₃, —CF₂H,     -   —COR^(A2),     -   —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂,     -   —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂,     -   —NH₂, —NHR^(A2), —NR^(A2) ₂,     -   —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂,     -   —SO₂R^(A2),     -   —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2); and         wherein R^(AR) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   —F, —Cl, —Br, —CN     -   —OH, —OR^(1A1),     -   —CF₃, —CF₂H,     -   —COR^(1A1),     -   —CH₂OH, —CH₂OR^(1A1), —CHR^(1A1)OH, CHR^(1A1)OR^(1A1)     -   —COOH, —COOR^(1A1), —CONH₂, —CONHR^(1A1), —CONR^(1A1) ₂,     -   —OCOR^(1A1), —OCONH₂, —OCONHR^(1A1), —OCONR^(1A1) ₂,     -   —NH₂, —NHR^(1A1), —NR^(1A1) ₂,     -   —SO₂NH₂, —SO₂NHR^(1A1) ₂, —SO₂NR^(1A1) ₂,     -   —SO₂R^(1A1),     -   —NHCOH, —NHCOR^(1A1), —NR^(1A1)COH and —NR^(1A1)COR^(1A1);         R^(AT) is selected from the group consisting of     -   —F, —CN     -   —OH, —OC₁₋₃alkyl,     -   —CF₃, —CF₂H,     -   —COC₁₋₃alkyl,     -   —COOH, —COOC₁₋₃alkyl, —CONH₂, —CONHC₁₋₃alkyl, —CON(C₁₋₃alkyl)₂,     -   —OCOC₁₋₃alkyl, —OCONH₂, —OCONHC₁₋₃alkyl, —OCON(C₁₋₃alkyl)₂,     -   —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)₂,     -   —SO₂NH₂, —SO₂NH(C₁₋₃alkyl)₂, —SO₂N(C₁₋₃alkyl)₂,     -   —SO₂(C₁₋₃alkyl),     -   —NHCOH, —NHCO(C₁₋₃alkyl), —N(C₁₋₃alkyl)COH and         —N(C₁₋₃alkyl)CO(C₁₋₃alkyl);         and pharmaceutically acceptable salts and solvates thereof.

In some embodiments of the second aspect,

R^(P1) and R^(P2) are each independently selected from

-   -   methyl and ethyl;         R^(P3) is selected from the group consisting of     -   methyl and ethyl,     -   4-membered or 5 membered heterocycloalkyl group linked to         phosphorus via a carbon atom in the ring, including a single         heteroatom independently selected from N, O and S,     -   —CF₃, —CH₂CF₃, —CH₂CF₂H, —CH₂CH₂OR^(PB),     -   —CH₂Q and —(CH₂)₂Q;         R^(A) and R^(B) together with the nitrogen atom to which they         are attached form a 5- or 6-membered heteroaryl,         heterocycloalkyl or heterocycloalkenyl group optionally         substituted with one or more groups selected from     -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2), and     -   R^(A1);         or an 8- to 10-membered heterobicyclyl group optionally         substituted with one or more groups selected from     -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1);     -   R^(A2) and     -   R^(A1).

In some embodiments of the second aspect, when P^(X) is P(CH₃)₃, —NR^(A)R^(B) is not selected from any of the groups (X1) to (X5), (X7) and (X12) to (X15);

and when P^(X) is P(C₂H₅)₃, —NR^(A)R^(B) is not selected from the groups (X1), (X6) to (X11), (X13) and (X14)

A third aspect of the present invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention. The pharmaceutical composition may also comprise a pharmaceutically acceptable diluent or excipient. The third aspect of the present invention also provides the use of a compound of the second aspect of the invention in a method of therapy.

Another aspect of the invention is a compound obtained by a method of synthesis as described herein.

For example, in some embodiments a compound is provided which is obtained by a method of reacting gold(I) complexes of formula III:

with a nitrogen containing derivative of general formula II:

wherein P^(X), R^(A) and R^(B) are as defined under the first aspect.

Another aspect of the invention is a compound obtainable by a method of synthesis as described herein.

For example, in some embodiments a compound is provided which is obtainable by a method of reacting gold(I) complexes of formula III:

with a nitrogen containing derivative of general formula II:

wherein P^(X), R^(A) and R^(B) are as defined under the first aspect.

Further aspects of the invention relate generally to the use of the compounds of the present invention to inhibit microbial growth, sensitize the inhibition of microbial growth, inhibit biofilm formation or development, disrupt existing biofilms, reduce the biomass of a biofilm, and sensitize a biofilm and microorganisms within the biofilm to an antimicrobial agent.

In one aspect the invention relates to a method for inhibiting biofilm formation, comprising exposing a biofilm-forming microorganism to an effective amount of a compound of the invention. In some embodiments a compound of the invention is coated, impregnated or otherwise contacted with a surface or interface susceptible to biofilm formation. In some embodiments, the surface is a surface of a medical device such as: medical or surgical equipment, an implantable medical device or prosthesis (for example, venous catheters, drainage catheters (e.g. urinary catheters), stents, pacemakers, contact lenses, hearing-aids, percutaneous glucose sensors, dialysis equipment, drug-pump related delivery cannula, prostheses such as artificial joints, implants such as breast implants, heart valves, medical fixation devices such as rods, screws, pins, plates, or devices for wound repair such as sutures, and wound dressings such as bandages). In particular embodiments, the biofilm or biofilm-forming microorganism is on a bodily surface of a subject and exposure of the biofilm or biofilm-forming microorganism to a compound of the invention is by administration of the compound of the invention to the subject. In such instances, the biofilm or biofilm-forming microorganism may be associated with an infection, disease or disorder suffered by the subject or to which the subject is susceptible. In a related aspect of the invention, a medical device (such as those exemplified above) coated or impregnated with a compound of the invention is provided.

In another aspect the invention relates to a method for reducing the biomass of a biofilm and/or promoting the dispersal of microorganisms from a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention.

In yet another aspect the invention relates to a method for dispersing or removing, removing, or eliminating a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention. In some embodiments the biofilm is an existing, preformed or established biofilm.

In a further aspect the invention relates to a method for killing microorganisms within a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention. In some embodiments the biofilm is an existing, preformed or established biofilm.

In a yet further aspect the invention relates to a method of sensitizing a microorganism in a biofilm to an antimicrobial agent by exposing the biofilm to an effective amount of a compound of the invention. In some embodiments the antimicrobial agent is an antibiotic (e.g. rifampicin, gentamicin, erythromycin, lincomycin, linezolid or vancomycin) or an antifungal agent.

In one aspect the invention relates to a compound of the invention for use in a method of dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an antimicrobial agent, treating or preventing an infection, disease or disorder caused by a biofilm, inhibiting the growth of a microbial persister cell, killing a microbial persister cell, or treating or preventing an infection, disease or disorder caused by or associated with a microbial persister cell.

In another aspect the invention relates to a compound of the invention for use in a method of treating or preventing an infection, disease or disorder treatable by dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an antimicrobial agent, inhibiting the growth of a microbial persister cell, killing a microbial persister cell, or treating or preventing an infection, disease or disorder caused by or associated with a microbial persister cell.

In some aspects, the biofilm comprises bacteria, such as, for example, multi-drug resistant bacteria. In some aspects the bacteria are Gram positive bacteria. In some aspects the bacteria are Gram negative bacteria. In particular examples, the biofilm comprises, consists essentially of, or consists of S. aureus. In some aspects, the S. aureus is methicillin-resistant S. aureus (MRSA). In some embodiments, the biofilm comprises, consists essentially of, or consists of A. baumannii. In other embodiments, the biofilm comprises, consists essentially of, or consists of K. pneumoniae. In other embodiments, the biofilm comprises, consists essentially of, or consists of one or more of the bacteria listed in Table 1 herein. In further embodiments, the biofilms comprise bacterial species, including but not limited to, Staphylococcus spp., Streptococcus spp., Enterococcus spp., Listeria spp. and Clostridium spp., Klebsiella spp., Acinetobacter spp., Pseudomonas spp., Burkholderia spp., Erwinia spp., Haemophilus spp., Neisseria spp., Escherichia spp, Enterobacter spp., Vibrio spp. and/or Actinobacillus spp.

In some aspects, biofilm comprises lower eukaryotes, such as yeast, fungi, and filamentous fungi, including, but not limited to Candida spp., Pneumocystis spp., Coccidioides spp., Aspergillus spp., Zygomycetes spp., Blastoschizomyces spp., Saccharomyces spp., Malassezia spp., Trichosporon spp. and Cryptococcus spp. Example species include C. albicans, C. glabrata, C. parapsilosis, C. dubliniensis, C. krusei, C. tropicalis, A. fumigatus, and C. neoforms.

The biofilm may comprise one species of microorganism, or comprise two or more species of microorganism, i.e. be a mixed species biofilm. The mixed species biofilms may include two or more species of bacteria, two or more species of lower eukaryote (e.g. two or more fungal species, such as unicellular fungi, filamentous fungi and/or yeast), and/or both bacteria and lower eukaryotes, such as one or more species of bacteria and one or more species of lower eukaryotes. For example, the methods, uses and compositions provided herein are applicable to biofilms comprising one or more species of bacteria and one or more species of fungi, such as a yeast, unicellular fungi and/or filamentous fungi. The mixed species biofilm may thus comprise 2, 3, 4, 5, 10, 15, 20 or more species of microorganism, and the microorganisms within the biofilm may be bacteria and/or lower eukaryotes, such as unicellular fungi, filamentous fungi and/or yeast.

In one aspect the invention relates to a method for killing persister cells or inhibiting the growth of a microbial persister cell, comprising exposing the persister cell to an effective amount of a compound of the invention.

In another aspect the invention relates to a method for reducing the number, density or proportion of persister cells in a microbial population, comprising exposing the persister cell to an effective amount of a compound of the invention. In some embodiments the number, density or proportion of persister cells in a microbial population is reduced by at least 10% compared to an otherwise identical population not exposed to a compound of the invention; for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.9%, or at least 99.99%.

In a further aspect the invention relates to a method of preventing the formation of microbial persister cells in a microbial population, the method comprising exposing the population to an effective amount of a compound of the invention.

In some aspects the persister cell is a bacterial or fungal persister cell. In some examples, the persister cell is a Gram negative bacterium. In some examples, the persister cell is a Gram positive bacterium. In some examples, the persister cell is a small colony variant. In particular embodiments, the persister cells are Staphylococcus spp. (including Staphylococcal SCVs), such as S. aureus (including methicillin resistant S. aureus (MRSA)), S. epidermidis, and S. capitis. In further embodiments, the persister cells are Pseudomonas spp. such as P. aeruginosa; Burkholderia spp. such as B. cepacia and B. pseudomallei; Salmonella serovars, including Salmonella Typhi; Vibrio spp. such as V. cholerae; Shigella spp.; Brucella spp. such as B. melitensis; Escherichia spp. such as E. coli; Lactobacillus spp. such as L. acidophilus; Serratia spp. such as S. marcescens; Neisseria spp. such as N. gonorrhoeae, or Candida spp., such as C. albicans.

The compounds of the invention can act together with other antimicrobial agents, allowing for increased efficacy of anti-microbial action. Accordingly, for any aspect described herein comprising exposing a biofilm, biofilm-forming microorganism, or a microbial persister cell to a compound of the invention, the present invention provides a corresponding further aspect comprising exposing the biofilm or biofilm-forming microorganism to a combination of compounds of the invention and at least one additional antimicrobial agent, such as, for example, an antibiotic or an anti-fungal agent. In particular examples, the antibiotic is selected from rifampicin, gentamicin, erythromycin, lincomycin and vancomycin.

The methods described herein may be performed, for example, in vivo, ex vivo, or in vitro.

Definitions

Microbe/Microorganism: The terms “microbe/microorganism” as used herein pertain to bacteria and lower eukaryotes, such as fungi, including yeasts, unicellular fungi and filamentous fungi.

Antimicrobial agent: The term “antimicrobial agent” as used herein pertains to any agent that, alone or in combination with another agent, is capable of killing or inhibiting the growth of one or more species of microorganism. Antimicrobial agents include, but are not limited to, antibiotics, antifungals, detergents, surfactants, agents that induce oxidative stress, bacteriocins and antimicrobial enzymes (e.g. lipases, proteinases, pronases and lyases) and various other proteolytic enzymes and nucleases, peptides and phage. Reference to an antimicrobial agent includes reference to both natural and synthetic antimicrobial agents. Examples of antimicrobial agents include fluoroquinolones, aminoglycosides, glycopeptides, lincosamides, cephalosporins and related beta-lactams, macrolides, nitroimidazoles, penicillins, polymyxins, tetracyclines, and any combination thereof. For example, the methods of the present invention can employ acedapsone; acetosulfone sodium; alamecin; alexidine; amdinocillin; amdinocillin pivoxil; amicycline; amifloxacin; amifloxacin mesylate; amikacin; amikacin sulfate; aminosalicylic acid; aminosalicylate sodium; amoxicillin; amphomycin; ampicillin; ampicillin sodium; apalcillin sodium; apramycin; aspartocin; astromicin sulfate; avilamycin; avoparcin; azithromycin; azlocillin; azlocillin sodium; bacampicillin hydrochloride; bacitracin; bacitracin methylene disalicylate; bacitracin zinc; bambermycins; benzoylpas calcium; berythromycin; betamicin sulfate; biapenem; biniramycin; biphenamine hydrochloride; bispyrithione magsulfex; butikacin; butirosin sulfate; capreomycin sulfate; carbadox; carbenicillin disodium; carbenicillin indanyl sodium; carbenicillin phenyl sodium; carbenicillin potassium; carumonam sodium; cefaclor; cefadroxil; cefamandole; cefamandole nafate; cefamandole sodium; cefaparole; cefatrizine; cefazaflur sodium; cefazolin; cefazolin sodium; cefbuperazone; cefdinir; cefepime; cefepime hydrochloride; cefetecol; cefixime; cefmenoxime hydrochloride; cefmetazole; cefmetazole sodium; cefonicid monosodium; cefonicid sodium; cefoperazone sodium; ceforanide; cefotaxime sodium; cefotetan; cefotetan disodium; cefotiam hydrochloride; cefoxitin; cefoxitin sodium; cefpimizole; cefpimizole sodium; cefpiramide; cefpiramide sodium; cefpirome sulfate; cefpodoxime proxetil; cefprozil; cefroxadine; cefsulodin sodium; ceftazidime; ceftibuten; ceftizoxime sodium; ceftriaxone sodium; cefuroxime; cefuroxime axetil; cefuroxime pivoxetil; cefuroxime sodium; cephacetrile sodium; cephalexin; cephalexin hydrochloride; cephaloglycin; cephaloridine; cephalothin sodium; cephapirin sodium; cephradine; cetocycline hydrochloride; cetophenicol; chloramphenicol; chloramphenicol palmitate; chloramphenicol pantothenate complex; chloramphenicol sodium succinate; chlorhexidine phosphanilate; chloroxylenol; chlortetracycline bisulfate; chlortetracycline hydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin hydrochloride; cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin; clindamycin hydrochloride; clindamycin palmitate hydrochloride; clindamycin phosphate; clofazimine; cloxacillin benzathine; cloxacillin sodium; chlorhexidine, cloxyquin; colistimethate sodium; colistin sulfate; coumermycin; coumermycin sodium; cyclacillin; cycloserine; dalfopristin; dapsone; daptomycin; demeclocycline; demeclocycline hydrochloride; demecycline; denofungin; diaveridine; dicloxacillin; dicloxacillin sodium; dihydrostreptomycin sulfate; dipyrithione; dirithromycin; doxycycline; doxycycline calcium; doxycycline fosfatex; doxycycline hyclate; droxacin sodium; enoxacin; epicillin; epitetracycline hydrochloride; erythromycin; erythromycin acistrate; erythromycin estolate; erythromycin ethylsuccinate; erythromycin gluceptate; erythromycin lactobionate; erythromycin propionate; erythromycin stearate; ethambutol hydrochloride; ethionamide; fleroxacin; floxacillin; fludalanine; flumequine; fosfomycin; fosfomycin tromethamine; fumoxicillin; furazolium chloride; furazolium tartrate; fusidate sodium; fusidic acid; ganciclovir and ganciclovir sodium; gentamicin sulfate; gloximonam; gramicidin; haloprogin; hetacillin; hetacillin potassium; hexedine; ibafloxacin; imipenem; isoconazole; isepamicin; isoniazid; josamycin; kanamycin sulfate; kitasamycin; levofuraltadone; levopropylcillin potassium; lexithromycin; lincomycin; lincomycin hydrochloride; lomefloxacin; lomefloxacin hydrochloride; lomefloxacin mesylate; loracarbef; mafenide; meclocycline; meclocycline sulfosalicylate; megalomicin potassium phosphate; mequidox; meropenem; methacycline; methacycline hydrochloride; methenamine; methenamine hippurate; methenamine mandelate; methicillin sodium; metioprim; metronidazole hydrochloride; metronidazole phosphate; mezlocillin; mezlocillin sodium; minocycline; minocycline hydrochloride; mirincamycin hydrochloride; monensin; monensin sodiumr; nafcillin sodium; nalidixate sodium; nalidixic acid; natainycin; nebramycin; neomycin palmitate; neomycin sulfate; neomycin undecylenate; netilmicin sulfate; neutramycin; nifuiradene; nifuraldezone; nifuratel; nifuratrone; nifurdazil; nifurimide; nifiupirinol; nifurquinazol; nifurthiazole; nitrocycline; nitrofurantoin; nitromide; norfloxacin; novobiocin sodium; ofloxacin; onnetoprim; oxacillin and oxacillin sodium; oximonam; oximonam sodium; oxolinic acid; oxytetracycline; oxytetracycline calcium; oxytetracycline hydrochloride; paldimycin; parachlorophenol; paulomycin; pefloxacin; pefloxacin mesylate; penamecillin; penicillins such as penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V, penicillin V benzathine, penicillin V hydrabamine, and penicillin V potassium; pentizidone sodium; phenyl aminosalicylate; piperacillin sodium; pirbenicillin sodium; piridicillin sodium; pirlimycin hydrochloride; pivampicillin hydrochloride; pivampicillin pamoate; pivampicillin probenate; polymyxin b sulfate; porfiromycin; propikacin; pyrazinamide; pyrithione zinc; quindecamine acetate; quinupristin; racephenicol; ramoplanin; ranimycin; relomycin; repromicin; rifabutin; rifametane; rifamexil; rifamide; rifampin; rifapentine; rifaximin; rolitetracycline; rolitetracycline nitrate; rosaramicin; rosaramicin butyrate; rosaramicin propionate; rosaramicin sodium phosphate; rosaramicin stearate; rosoxacin; roxarsone; roxithromycin; sancycline; sanfetrinem sodium; sarmoxicillin; sarpicillin; scopafungin; sisomicin; sisomicin sulfate; sparfloxacin; spectinomycin hydrochloride; spiramycin; stallimycin hydrochloride; steffimycin; streptomycin sulfate; streptonicozid; sulfabenz; sulfabenzamide; sulfacetamide; sulfacetamide sodium; sulfacytine; sulfadiazine; sulfadiazine sodium; sulfadoxine; sulfalene; sulfamerazine; sulfameter; sulfamethazine; sulfamethizole; sulfamethoxazole; sulfamonomethoxine; sulfamoxole; sulfanilate zinc; sulfanitran; sulfasalazine; sulfasomizole; sulfathiazole; sulfazamet; sulfisoxazole; sulfisoxazole acetyl; sulfisboxazole diolamine; sulfomyxin; sulopenem; sultamricillin; suncillin sodium; talampicillin hydrochloride; teicoplanin; temafloxacin hydrochloride; temocillin; tetracycline; tetracycline hydrochloride; tetracycline phosphate complex; tetroxoprim; thiamphenicol; thiphencillin potassium; ticarcillin cresyl sodium; ticarcillin disodium; ticarcillin monosodium; ticlatone; tiodonium chloride; tobramycin; tobramycin sulfate; tosufloxacin; trimethoprim; trimethoprim sulfate; trisulfapyrimidines; troleandomycin; trospectomycin sulfate; tyrothricin; vancomycin; vancomycin hydrochloride; virginiamycin; zorbamycin; bifonazolem; butoconazole; clotrimazole; econazole; fenticonazole; isoconazole; ketoconazole; miconazolel omoconazolel oxiconazolel sertaconazolel sulconazolel tioconazolel; albaconazole; fluconazole; isavuconazole; itraconazole; posaconazole; ravuconazole; terconazole; voriconazole; abafungin; amorolfin; butenafine; naftifine; terbinafine; anidulafungin; caspofungin; and micafungin.

Biofilm: The term “biofilm” as used herein pertains to any three-dimensional, matrix-encased microbial community displaying multicellular characteristics. Accordingly, the term biofilm includes surface-associated biofilms as well as biofilms in suspension, such as flocs and granules. Biofilms may comprise a single microbial species or may be mixed species complexes, and may include bacteria as well as fungi, algae, protozoa, or other microorganisms.

Reducing the biomass of a biofilm: The term “reducing the biomass of a biofilm” is used herein to mean reducing the biomass of an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the biofilm biomass of the area immediately before exposure to a compound of the invention. In some embodiments the “biomass” is the mass of cells present in the area of biofilm in addition to the extracellular polymeric substance (EPS) of the biofilm matrix. In some embodiments the “biomass” is only the mass of cells present in the area of biofilm (that is, the mass of the EPS is not counted as “biomass”). In some embodiments the biomass of the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the biofilm biomass of the area immediately before exposure to a compound of the invention, the mass of the otherwise identical area of a biofilm which has not been exposed to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the biofilm biomass of the area immediately before exposure to a compound of the invention. In some embodiments the area of biofilm compared is 10⁻⁶ m²; in other embodiments the area of biofilm compared is 10⁻⁵ m², 10⁻⁴ m², or 10⁻³ m². In some embodiments a biofilm whose biomass has been reduced by at least 95% is deemed to have been “eliminated”, “dispersed” or “removed”. In some embodiments a biofilm whose biomass has been reduced by at least 99% is deemed to have been “eliminated”, “dispersed” or “removed”. In some embodiments a biofilm whose biomass has been reduced by at least 99.9% is deemed to have been “eliminated”, “dispersed” or “removed”. In some embodiments the change in biofilm biomass is assessed by a method comprising the steps of: i) washing the area of biofilm to remove non-adherent (planktonic) microorganisms, ii) assessing the area of biofilm biomass (i.e. the biomass “immediately before exposure to a compound of the invention”), iii) exposing the area of biofilm (or an otherwise identical area) to an effective amount of a compound of the invention for a period of time (for example, 24 hours), iv) washing the biofilm to remove non-adherent (planktonic) microorganisms, and v) assessing the area of biofilm biomass to obtain the ‘post-exposure’ biomass.

Promoting the dispersal of microorganisms from a biofilm: The term “promoting the dispersal of microorganisms from a biofilm” is used herein to mean reducing the number of microorganisms present in an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the number of microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the number of microorganisms in the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the number of microorganisms present in the area immediately before exposure to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the number of microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the change in number of microorganisms in an area of biofilm is assessed by a method comprising the steps of: i) washing the biofilm to remove non-adherent (planktonic) microorganisms, ii) counting the remaining microorganisms to obtain a ‘pre-exposure’ microorganism count (i.e. the count “immediately before exposure to a compound of the invention”), iii) exposing the biofilm to an effective amount of a compound of the invention for a period of time (for example, 24 hours), iv) washing the biofilm to remove non-adherent (planktonic) microorganisms, and v) counting the remaining microorganisms to obtain the ‘post-exposure’ microorganism count. In some embodiments a biofilm where number of microorganisms in an area has been reduced by at least 95% is deemed to have been “eliminated”, “dispersed” or “removed”. In some embodiments a biofilm where number of microorganisms in an area has been reduced by at least 99% is deemed to have been “eliminated”, “dispersed” or “removed”. In some embodiments a biofilm where number of microorganisms in an area has been reduced by at least 99.9% is deemed to have been “eliminated”, “dispersed” or “removed”.

Killing microorganisms within a biofilm: The term “killing microorganisms within a biofilm” is used herein to mean reducing the number of live microorganisms present in an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the number of live microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the biofilm is an existing, preformed or established biofilm. In some embodiments the number of live microorganisms in the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the number of live microorganisms present in the area immediately before exposure to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the number of live microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the change in number of microorganisms in an area of biofilm is assessed by a method comprising the steps of: i) washing the area biofilm to remove non-adherent (planktonic) microorganisms, ii) manually disperse the biofilm into solution (using, for example, scraping, sonication, and vortexing), iii) prepare serial dilutions, plate, and culture to estimate the number of colony forming unit (cfu) in the area of biofilm, iv) provide an otherwise identical area of biofilm and expose it to an effective amount of a compound of the invention for a period of time (for example, 24 hours), v) manually disperse the biofilm and estimate cfu as described above to obtain the ‘post-exposure’ microorganism count. The viability of the biofilm can be also assessed by allowing the biofilm to re-grow in compound free medium and assessing planktonic growth.

Dispersal: The term “dispersal” as used herein pertains to any to a biofilm and microorganisms making up a biofilm means the process of detachment and separation of cells and a return to a planktonic phenotype or behaviour of the dispersing cells.

Exposing: The term “exposing” as used herein means generally bringing into contact with. Exposure of a biofilm or biofilm-forming microorganism to an agent (e.g. a compound of the invention) includes administration of the agent to a subject harbouring the microorganism or biofilm, or otherwise bringing the microorganism or biofilm into contact with the agent itself, such as by contacting a surface on which the biofilm or biofilm-forming microorganism are present with the agent. In some embodiments, the biofilm or biofilm-forming microorganisms are exposed to a compound of the invention by coating, impregnating or otherwise contacting a surface or interface susceptible to biofilm formation to an effective amount of the compound. Surfaces that may be exposed, coated, or impregnated with a compound of the invention include those present in a range of industrial and domestic settings, including but not limited to, domestic, medical or industrial settings (e.g. medical and surgical devices, and surfaces within hospitals, processing plants and manufacturing plants), as well as internal and external surfaces of the body of a subject. In the present disclosure the terms “exposing”, “administering” and “contacting” and variations thereof may, in some contexts, be used interchangeably.

Inhibiting: The term “inhibiting” and variations thereof such as “inhibition” and “inhibits” as used herein in relation to microbial growth refers to any microbiocidal or microbiostatic activity of an agent (e.g. a compound of the invention) or composition. Such inhibition may be in magnitude and/or be temporal or spatial in nature. Inhibition of the growth of a microorganism by an agent can be assessed by measuring growth of the microorganism in the presence and absence of the agent. The growth can be inhibited by the agent by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the growth of the same microorganism that is not exposed to the agent.

The term “inhibiting” and variations thereof such as “inhibition” and “inhibits” as used herein in relation to biofilms means complete or partial inhibition of biofilm formation and/or development and also includes within its scope the reversal of biofilm development or processes associated with biofilm formation and/or development. Further, inhibition may be permanent or temporary. The inhibition may be to an extent (in magnitude and/or spatially), and/or for a time, sufficient to produce the desired effect. Inhibition may be prevention, retardation, reduction or otherwise hindrance of biofilm formation or development. Such inhibition may be in magnitude and/or be temporal or spatial in nature. Inhibition of the formation or development of a biofilm by a compound of the invention can be assessed by measuring biofilm mass or microbial growth in the presence and absence of a compound of the invention. The formation or development of a biofilm can be inhibited by a compound of the invention by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the formation or development of a biofilm that is not exposed to a compound of the invention.

Sensitize: The terms “sensitize” or “sensitizing” as used herein mean making a biofilm or microorganisms within a biofilm more susceptible to an antimicrobial agent. The sensitizing effect of a compound of the invention, on a biofilm or microorganisms within the biofilm can be measured as the difference in the susceptibility of the biofilm or microorganisms (as measured by, for example, microbial growth or biomass of the biofilm) to a second antimicrobial agent with and without administration of the compound. The sensitivity of a sensitized biofilm or microorganism (i.e. for example, a biofilm or microorganism exposed to an agent such as a compound of the invention) to a antimicrobial agent can be increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500% or more compared to the sensitivity of an unsensitized biofilm or microorganism (i.e. a biofilm or microorganism not exposed to the agent). In some embodiments sensitizing effect of a compound of the invention on a biofilm or microorganisms within the biofilm can be measured by the difference in Minimum Inhibitory Concentration (MIC) of a second antimicrobial administered either in combination with a compound of the invention, or alone. For example, in some embodiments the MIC of a combination of a compound of the invention and the second antimicrobial is at least 10% lower than the MIC of the second antimicrobial administered alone; such as at least 20% lower, at least 30% lower, at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower, at least 90% lower, at least 95% lower, at least 99% lower, or at least 99.9% lower than the MIC of the second antimicrobial administered alone. The sensitization of a microorganism may also occur outside of a biofilm.

Surface: The term “surface” as used herein includes both biological surfaces and non-biological surfaces. Biological surfaces typically include surfaces both internal (such as organs, tissues, cells, bones and membranes) and external (such as skin, hair, epidermal appendages, seeds, plant foliage) to an organism. Biological surfaces also include other natural surfaces such as wood or fibre. A non-biological surface may be any artificial surface of any composition that supports the establishment and development of a biofilm. Such surfaces may be present in industrial plants and equipment, and include medical and surgical equipment and medical devices, both implantable and non-implantable. Further, for the purposes of the present disclosure, a surface may be porous (such as a membrane) or non-porous, and may be rigid or flexible.

Infection, disease or disorder caused by a biofilm/infection, disease or disorder caused by or associated with a microbial persister cell: The term “Infection, disease or disorder caused by a biofilm” as used herein is used to describe conditions, diseases and disorders associated with, characterised by, or caused by biofilms and biofilm-forming microorganisms. Similarly, the term “Infection, disease or disorder caused by or associated with a microbial persister cell” as used herein is used to describe conditions, diseases and disorders associated with, characterised by, or caused by microbial persister cells. For example, a variety of microbial infections are known to be associated with biofilm formation and/or persister cells, such as cellulitis, impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries, periodontitis, bacterial prostatitis and infections associated with surgical procedures or burns. For example, S. aureus and S. epidermidis cause or are associated with cellulitis, impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries and infections associated with surgical procedures or burns. In other examples, K. pneumoniae can cause or be associated with pneumonia, sepsis, community-acquired pyogenic liver abscess (PLA), urinary tract infection, and infections associated with surgical procedures or burns. In further examples, A. baumannii can cause or be associated with bacteremia, pneumonia, meningitis, urinary tract infection, and infections associated with wounds. In still further examples, P. aeruginosa can cause or be associated with respiratory tract infections (including pneumonia), skin infections, urinary tract infections, bacteremia, infection of the ear (including otitis media, otitis externa and otitis interna), endocarditis and bone and joint infections such as osteomyelitis. Candida spp. such as C. albicans, Cryptococcus spp. such as C. neoformans, as well as other fungi such as Trichosporon spp., Malassezia spp., Blastoschizomyces spp., Coccidioides spp. and Saccharomyces spp. (e.g. S. cerevisiae) may cause or be associated with infections related to the implantation or use of medical or surgical devices, such as catheterization or implantation of heart valves.

Persister cell(s): The term “persister cell(s)” as used herein pertains to metabolic variants of wild type microbial cells that are phenotypically characterized by their slow growth rate, which is typically 30%, 25%, 20%, 15%, 10%, 5% or less of the growth rate of the wild-type counterpart. In some embodiments, the persister cells are dormant and have, for example, no detectable cell division in a 24 hour period. Further, persister cells typically form colonies that are approximately 30%, 25%, 20%, 15%, 10%, 5% or less of the size of the colonies formed by their wild-type counterparts. Reference to persister cells includes reference to persister cells of any microbial genera or species, including, but not limited to, bacterial and lower eukaryotic, such as fungal, including yeast, persister cells. In some examples, the persister cell is a Gram negative bacterium. In some examples, the persister cell is a Gram positive bacterium. Exemplary persister cells include, but are not limited to, those of Staphylococcus spp., such as S. aureus, S. epidermidis, and S. capitis; Pseudomonas spp. such as P. aeruginosa; Burkholderia spp. such as B. cepacia and B. pseudomallei; Salmonella serovars, including Salmonella Typhi; Vibrio spp. such as V. cholerae; Shigella spp.; Brucella spp. such as B. melitensis; Escherichia spp. such as E. coli; Lactobacillus spp. such as L. acidophilus; Serratia spp. such as S. marcescens; Neisseria spp. such as N. gonorrhoeae, as well as Candida spp., such as C. albicans.

C₁₋₆ alkyl: The term “C₁₋₆ alkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 6 carbon atoms.

Examples of saturated alkyl groups include, but are not limited to, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅) and hexyl (C₆).

Examples of saturated linear alkyl groups include, but are not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl (C₅) and n-hexyl (C₆).

Examples of saturated branched alkyl groups include iso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅), neopentyl (C₅), iso-hexyl (C₆) and neohexyl (C₆).

C₂₋₆ alkenyl: The term “C₂₋₆ alkenyl” as used herein, pertains to a C₂₋₆ alkyl group having one or more carbon-carbon double bonds. Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃), 2-propenyl (allyl, —CH—CH═CH₂) and isopropenyl (1-methylvinyl, —C(CH₃)═CH₂).

C₂₋₆ alkynyl: The term “C₂₋₆ alkynyl” as used herein, pertains to a C₂₋₆ alkyl group having one or more carbon-carbon triple bonds. Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (—C≡CH) and 2-propynyl (propargyl, —CH₂—C≡CH).

C₃₋₆ cycloalkyl: the term “C₃₋₆ cycloalkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic core having 3, 4, 5 or 6 atom in the cyclic core all of which are carbon atoms. Examples of C₃₋₆ cycloalkyl include, but are not limited to, cyclopropyl, cyclohexyl and cyclopentyl.

C₅₋₆ cycloalkenyl: The term “C₅₋₆ cycloalkenyl” as used herein, pertains to a C₃₋₆ cycloalkyl group having one or more carbon-carbon double bonds.

C₄₋₆ heterocycloalkyl: The term “C₄₋₆ heterocycloalkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 4 to 6 ring atoms, of which from 1 to 3 are ring heteroatoms selected from O, S and N. In this context, the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms

Examples of monocyclic heterocycloalkyl groups include, but are not limited to, those derived from:

N₁: azetidine (C₄), pyrrolidine (tetrahydropyrrole) (C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆), dihydropyridine (C₆), tetrahydropyridine (C₆); O₁: oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole (dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆), pyran (C₆); S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅), thiane (tetrahydrothiopyran) (C₆); O₂: dioxolane (C₅), dioxane (C₆); N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline (C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆); N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆); N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆); N₂O₁: oxadiazine (C₆); O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and, N₁O₁S₁: oxathiazine (C₆).

C₅₋₆ heterocycloalkenyl: The term “OC₅₋₆ heterocycloalkenyl” as used herein, pertains to a C₅₋₆ heterocycloalkyl group having one or more carbon-carbon or carbon-nitrogen double bonds.

Heterobicyclyl: The term “heterobicyclyl” as used herein, pertains to a bicyclic ring, wherein 1, 2, or 3 ring carbons are replaced with a heteroatom selected from the group consisting of O, S and N. In some embodiments, one of the rings is aromatic. The bicylic rings may be spiro or fused. Examples of a heterobicyclic group include, but are not limited to, 2,5-diaza-bicyclo[2.2.1]hept-2-yl, 7-aza-bicyclo[2.2.1]hept-7-yl, 1,3-dihydro-isoindolyl, 3,4-dihydro-1H-isoquinolinyl, octahydro-cyclopenta[c]pyrrolyl and the like

C₅₋₆ heteroaryl: the term C₅₋₆ heteroaryl as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of an aromatic structure having between one and three atoms that are not carbon forming part of said ring. Wherein, those atoms that are not carbon can be chosen independently from the list nitrogen, oxygen and sulphur.

Examples of C₅₋₆ heteroaryl groups include, but are not limited to, groups derived from:

N₁: pyridine (C₆); N₁O₁: oxazole (C₅), isoxazole (C₅); N₂O₁: oxadiazole (furazan) (C₅); N₂S₁: thiadiazole (C₅) N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅), pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C₆); N₃: triazole (C₅).

FURTHER EMBODIMENTS

In some embodiments, P^(X) is P1.

In some embodiments, R^(P1) is methyl. In other embodiments, R^(P1) is ethyl.

In some embodiments, R^(P2) is methyl. In other embodiments, R^(P2) is ethyl.

In some embodiments, both R^(P1) and R^(P2) are methyl. In other embodiments, both R^(P1) and R^(P2) are ethyl. In further embodiments, R^(P1) is methyl and R^(P2) is ethyl.

In some embodiments, R^(P1) is isopropyl. In some embodiments, R^(P1) is phenyl. In some embodiments, both R^(P1) and R^(P2) are isopropyl. In some embodiments, both R^(P1) and R^(P2) are phenyl.

In some embodiments, R^(P1) is methyl, R^(P2) is phenyl and R^(P3) is selected from methyl and phenyl.

In some embodiments, R^(P3) is methyl. In other embodiments, R^(P3) is ethyl.

In some embodiments, R^(P3) is isopropyl. In some embodiments, R^(P3) is t-butyl. In some embodiments, R^(P3) is cyclopentyl. In some embodiments, R^(P3) is phenyl.

In some embodiments, P^(X) is PEt₃.

In some embodiments, P^(X) is PEt₂Me.

In some embodiments, P^(X) is PEtMe₂.

In some embodiments, P^(X) is PMe₃.

In some embodiments, P^(X) is P(Ph)₃.

In some embodiments, P^(X) is P(i-Pr)₃.

In some embodiments, P^(X) is P(Me)(Ph)₂.

In some embodiments, P^(X) is P(Ph)(Me)₂.

In some embodiments, R^(P3) is a 4-membered or 5-membered heterocycloalkyl group linked to phosphorus via a carbon atom in the ring, including a single heteroatom independently selected from N, O and S. In these embodiments, R^(P3) may be selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl and thiolanyl. In some of these embodiments, R^(P3) may be oxetanyl or tetrahydrofuranyl.

In some embodiments, P^(X) is:

In some embodiments, R^(P3) is selected from the group consisting of —CF₃, —CH₂CF₃, —CH₂CF₂H and —CH₂CH₂OR^(PB). In some of these embodiments, R^(PB) may be a linear or branched C₁₋₆ alkyl, e.g. methyl.

In some embodiments, P^(X) is selected from:

In some embodiments, R^(P3) is selected from the group consisting of —CH₂Q and —(CH₂)₂Q. In some of these embodiments, R^(P3) is —CH₂Q. In other of these embodiments, R^(P3) is —(CH₂)₂Q.

In any of these embodiments, Q is a C₅₋₆ heteroaryl group, optionally substituted with one or more groups R^(PA). In some of these embodiments, Q may be unsubstituted. In other of these embodiments, Q may be substituted, and in particular, if Q comprises a N ring atom, this may be substituted by a methyl group.

In some embodiments, Q is independently selected from

wherein Q¹ is independently selected from O, S and NR^(PE); each of Q² to Q⁴ is independently selected from N and CR^(PA); two of Q⁵ to Q⁹ is selected from CR^(PA), one other of Q⁵ to Q⁹ is selected from N and the remainder are selected from N, CH and CR^(PA).

In some embodiments, P^(X) is selected from:

In some embodiments, P^(X) is P2.

In some embodiments, R^(P4) is methyl. In other embodiments, R^(P4) is ethyl.

In some embodiments, m is 1. In other embodiments, m is 2. In further embodiments, m is 3.

In some embodiments, the ring in P2 is not substituted. In other embodiments, there is one R^(M) substituent on the ring in P2. In further embodiments, there are two R^(M) substituents on the ring in P2.

In some embodiments, R^(M) is R^(PC) and R^(PC) may be methyl. In other embodiments, R^(M) is OH. In further embodiments, R^(PC) is OMe.

In some embodiments, P^(X) is selected from:

In some embodiments, P^(X) is P3.

In some embodiments, -L^(B)- is methylene. In other embodiments, -L^(B)- is ethylene.

When -L^(B)- is present, R^(P4) is absent and R¹ is selected from N, CH and CR^(PC). In some of these embodiments, R¹ is N. In other of these embodiments, R¹ is CH. In further of these embodiments, R¹ is CR^(PC). In some embodiments, R^(PC) is unsubstituted C₁₋₃ alkyl, e.g. methyl.

When L^(B) is absent, in some embodiments R¹ is selected from the group consisting of O, NR^(Z), and SO₂. In these embodiments, R^(Z) may be selected from H and C₁₋₃ alkyl e.g. methyl.

When L^(B) is absent, in some embodiments R¹ is selected from the group consisting of CH₂, CHF, CF₂ and CHR^(PC). In some of these embodiments, R¹ is CH₂. In other of these embodiments, R¹ is CHF. In other of these embodiments, R¹ is CF₂. In further of these embodiments, R¹ is CHR^(PC). In some embodiments, R^(PC) is unsubstituted C₁₋₃ alkyl, e.g. methyl.

In some embodiments, P^(X) is selected from:

R_(A), R^(B)

In some embodiments R^(A) is linear or branched C₁₋₆alkyl optionally substituted with one or more groups R^(AL); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is linear or branched C₁₋₆alkyl optionally substituted with one or more groups R^(AL); and R^(B) is selected from —CO(C₁₋₆alkyl) and —SO₂R^(A2).

In some embodiments R^(A) is unsubstituted linear or branched C₁₋₆alkyl; and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is unsubstituted linear or branched C₁₋₆alkyl; and R^(B) is selected from —CO(C₁₋₆alkyl) and —SO₂R^(A2).

In the above embodiments, R^(AL) may be selected from

-   -   —F, —CN     -   —OH, —OR^(A2),     -   —NH₂, —NHR^(A2), —NR^(A2) ₂,     -   —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2).

In the above embodiments, R^(AL) may be selected from

-   -   —F,     -   —OH, —OR^(A2),     -   —NH₂, —NHR^(A2) and —NR^(A2) ₂.

In some embodiments R^(A) is C₅₋₆heteroaryl, optionally substituted with one or more groups R^(A1); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments, R^(A) is C₅heteroaryl, optionally substituted with one or more groups R^(A1) (e.g. C₁₋₆ alkyl, such as methyl); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is C₆heteroaryl, optionally substituted with one or more groups R^(A) (e.g. C₁₋₆ alkyl, such as methyl); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is C₁₋₃alkyl substituted by phenyl or C₅₋₆heteroaryl, which groups may optionally be substituted with one or more groups R^(A1); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is C₁₋₃alkyl (e.g. methyl) substituted by C₅heteroaryl which is optionally substituted with one or more groups R^(A1); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is C₁₋₃alkyl (e.g. methyl) substituted b+y C₆heteroaryl which is optionally substituted with one or more groups R^(A1); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments R^(A) is C₁₋₃alkyl (e.g. methyl) substituted by phenyl which is optionally substituted with one or more groups R^(A1); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2).

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from

NR^(A)R^(B)

In some embodiments, —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from

-   -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2), and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group containing up to two heteroatoms in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); optionally substituted with one or more groups selected from

-   -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2), and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group containing up to two heteroatoms in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); substituted with one or two oxo groups and optionally further substituted with one or more groups selected from

-   -   phenyl optionally substituted with one or more groups R^(A1),         and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group containing one heteroatom in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); substituted with one or two oxo groups and optionally further substituted with one or more groups selected from

-   -   phenyl optionally substituted with one or more groups R^(A1),         and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group containing one heteroatom in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); substituted with one or two oxo groups and optionally further substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl; and     -   phenyl optionally substituted with one or more groups selected         from F, Cl, Br, CN, OH, O(C₁₋₆alkyl), COOH and COO(C₁₋₆alkyl).

In some embodiments, —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group containing one heteroatom in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); substituted with one or two oxo groups and optionally further substituted with one or more groups selected from

-   -   C₁₋₃alkyl; and     -   phenyl optionally substituted with one or more groups selected         from F, Cl, OH and O(C₁₋₆alkyl).

In some embodiments, —NR^(A)R^(B) is the group (A1)

wherein X¹ is selected from C═O and CR^(4A)R^(4B); X² is selected from O, CR^(4A)R^(4B) and NR^(X); and one of X³ and X⁴ is selected from C═O, CR^(4A)R^(4B) and SO₂, with the other group of X³ and X⁴ being selected from CR^(4A)R^(4B); wherein R^(X) is selected from —H and —R^(A5); each R^(4A) and R^(4B) is independently selected from

-   -   —H,     -   linear or branched C₁₋₄alkyl optionally substituted with one or         more groups R^(AL),     -   phenyl, optionally substituted with one or more groups R^(A1),     -   C₅₋₆heteroaryl optionally substituted with one or more groups         R^(A1),     -   independently geminal R^(4A) and R^(4B) groups may be joined to         form a 5- or 6-membered alicyclic or 5- or 6-membered         heteroalicyclic group optionally substituted with one or more         groups R^(AL), and     -   independently two vicinal R^(4A) groups may be joined to form a         5- or 6-membered alicyclic, heteroalicyclic, aromatic or         heteroaromatic group optionally substituted with one or more         groups R^(A1);         and R^(A5) is selected from the group consisting of     -   linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl         optionally substituted with one or more groups R^(AL),     -   C₃₋₆cycloalkyl or C₄₋₆heterocycloalkyl optionally substituted         with one or more groups R^(AT),     -   phenyl, optionally substituted with one or more groups R^(A1),     -   C₅₋₆heteroaryl optionally substituted with one or more groups         R^(A1), or     -   except when each of R^(P1) to R^(P3) is selected from ethyl,         R^(A5) may be joined to a vicinal R^(4A) or R^(4B) group to form         a 5- or 6-membered heterocyclic or heteroaromatic group         optionally substituted with one or more groups R^(A1);

In some embodiments, —NR^(A)R^(B) is the group (A2)

wherein V¹ is selected from C═O and SO₂; V² is selected from O, NR^(X) and CR^(4A)R^(4B); with the proviso that when V¹ is SO₂, V² cannot be O; wherein R^(X), R^(4A) and R^(4B) are as defined above.

In some embodiments, —NR^(A)R^(B) is the group (A4)

wherein Z¹ is selected from C═O and CR^(4A)R^(4B); Z² and Z³ are each independently selected from the group consisting of

-   -   O,     -   CR^(4A)R^(4B), C═O and     -   NR^(X),         with the proviso that any two adjacent groups of Z¹ to Z⁴ cannot         both be O, cannot both be C═O and cannot both be NR^(X);         Z⁴ is selected from CR^(4A)R^(4B), and NR^(X);         and Z⁵ is selected from C═O and SO₂;         with R^(4A), R^(4B) and R^(X) being as defined above.

In some embodiments, —NR^(A)R^(B) is the group (A5)

wherein a dotted line indicates that a bond may be present or absent; and W¹ to W⁴ are each independently selected from CH and CR^(A1).

In some embodiments, —NR^(A)R^(B) is the group (A6)

wherein W⁵ to W⁸ are each independently selected from CH and CR^(A1).

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from

-   -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2), and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is selected from a 5- or 6-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); optionally substituted with one or more groups selected from

-   -   phenyl optionally substituted with one or more groups R^(A1);     -   R^(A2), and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B); optionally substituted with one or more groups selected from

-   -   phenyl optionally substituted with one or more groups R^(AL),     -   R^(A2), and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of —NR^(A)R^(B); optionally substituted with one or more groups R^(A1).

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing one or two heteroatoms in the ring in addition to the N atom of —NR^(A)R^(B), the heteroatoms being N atoms; wherein the heteroaryl group is optionally substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl,     -   F, Cl, Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing one heteroatom in the ring in addition to the N atom of —NR^(A)R^(B), wherein both heteroatoms are N atoms; and wherein the heteroaryl group is optionally substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl,     -   F, Cl, Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing two heteroatoms in the ring in addition to the N atom of —NR^(A)R^(B), wherein both heteroatoms are N atoms; and wherein the heteroaryl group is optionally substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl,     -   F, Cl, Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing one or two heteroatoms in the ring in addition to the N atom of —NR^(A)R^(B), the heteroatoms being N atoms; wherein the heteroaryl group is optionally substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl,     -   F, Cl, Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of —NR^(A)R^(B); optionally substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl,     -   F, Cl, Br,     -   —CN     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH and —COO(C₁₋₆alkyl).

In some embodiments, —NR^(A)R^(B) is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of —NR^(A)R^(B); optionally substituted with one or more groups selected from

-   -   linear or branched C₁₋₆alkyl,     -   —CN     -   —CF₃, —CF₂H and —CH₂F.

In some embodiments, —NR^(A)R^(B) is the group (A3)

wherein one group from Y¹ to Y⁴ is CR³, another is N and the remainder are independently selected from CR³ and N.

In some embodiments, —NR^(A)R^(B) is the group (A7)

wherein one of Y⁵, Y⁶ and Y⁷ is selected from N and CR^(Y1); and the other two of Y⁵, Y⁶ and Y⁷ are each independently selected from CR^(Y1); wherein R^(Y1) is selected from

-   -   —H;     -   C₁₋₆ linear or branched unsubstituted alkyl;     -   —F, —Cl, —Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, —NR^(A)R^(B) is the group (A7)

wherein one of Y⁵, Y⁶ and Y⁷ is selected from N and CH; a second of Y⁵, Y⁶ and Y⁷ is CH and the third of Y⁵, Y⁶ and Y⁷ is selected from CH and CR¹; wherein R¹ is selected from

-   -   —H;     -   C₁₋₆ linear or branched unsubstituted alkyl;     -   —F, —Cl, —Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, P^(X) is (P1); R^(P1) and R^(P2) are each independently selected from methyl and ethyl;

R^(P3) is selected from

-   -   methyl, ethyl, n-propyl,     -   -Q^(A), —CH₂Q^(A), —(CH₂)₂Q^(A),     -   wherein Q^(A) is selected from         -   cyclopropyl,         -   4- or 5-membered heterocycloalkyl groups containing one or             two heteroatoms selected from NR^(Z), O and S, and         -   4- or 5-membered cycloalkyl groups;     -   wherein R^(Z) is selected from the group consisting of         -   H, C₁₋₃alkyl, COC₁₋₃alkyl and SO₂C₁₋₃alkyl;             and             —NR^(A)R^(B) is the group (A7)

wherein one of Y⁵, Y⁶ and Y⁷ is selected from N and CR^(Y1); and the other two of Y⁵, Y⁶ and Y⁷ are each independently selected from CR^(Y1); wherein R^(Y1) is selected from

-   -   —H;     -   C₁₋₆ linear or branched unsubstituted alkyl;     -   —F, —Cl, —Br,     -   —CN,     -   —CF₃, —CF₂H, —CH₂F,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH, —COO(C₁₋₆alkyl) and —CON(C₁₋₆alkyl)₂.

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, NR^(A)R^(B) is an imidazolyl group, bearing a C substituent which is the group (B1)

(i.e. ethyl substituted by COR^(B3) and NR^(B1)R^(B2)) wherein R^(B1) is selected from the group consisting of

-   -   —H,     -   —COR^(A2), —CONR^(A2), CO₂R^(A2), and     -   —SO₂R^(A2);         R^(B2) is selected from —H, and linear or branched C₁₋₄alkyl;         and         R^(B3) is selected from the group consisting of     -   —OH, —OR^(A2),     -   —NH₂, —NHR^(A2) and —NR^(A2) ₂.

In some embodiments, —NR^(A)R^(B) is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from

-   -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2) and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is a 9-membered heterobicyclyl group optionally substituted with one or more groups selected from

-   -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2) and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

-   -   oxo,     -   phenyl optionally substituted with one or more groups R^(A1),     -   R^(A2) and     -   R^(A1).

Herein, a “5,6” fused ring system indicates that the N of —NR^(A)R^(B) lies within a 5-membered ring which is fused to a 6-membered ring.

In some embodiments, —NR^(A)R^(B) is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

-   -   oxo,     -   linear or branched C₁₋₆alkyl,     -   —F, —Cl, —Br,     -   —CN,     -   —OH, —O(C₁₋₆alkyl),     -   —COOH and —COO(C₁₋₆alkyl).

In some embodiments, —NR^(A)R^(B) is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

-   -   oxo,     -   linear or branched C₁₋₆alkyl,     -   —OH and —O(C₁₋₆alkyl).

In some embodiments, —NR^(A)R^(B) is a 10-membered 6,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

-   -   oxo, and     -   R^(A1).

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, —NR^(A)R^(B) is selected from

In some embodiments, the compound is a compound according to formula (Ia)

wherein R^(A) and R^(B) are as defined above.

In some embodiments, the compound is a compound according to formula (Ib)

wherein P^(X) is as defined above; and NR^(A)R^(B) is selected from:

In some embodiments, the compound is selected from:

Particular embodiments of the invention are shown in the examples.

Further compounds of the invention include:

Bacterial Infections

Bacteria that cause infection of humans include, but are not limited to, those set out below in Table 1.

TABLE 1 Genus Important species Gram negative/positive Bordetella Bordetella pertussis Gram-negative Borrelia Borrelia burgdorferi Gram-negative Brucella Brucella abortus Gram-negative Brucella canis Brucella melitensis Brucella suis Burkholderia Burkholderia cepacia Gram-negative Campylobacter Campylobacter jejuni Gram-negative Chlamydia and Chlamydia pneumoniae (not Gram-stained) Chlamydophila Chlamydia trachomatis Chlamydophila psittaci Clostridium Clostridium botulinum Gram-positive Clostridium difficile Clostridium perfringens Clostridium tetani Corynebacterium Corynebacterium diphtheriae Gram-positive Enterobacter Enterobacter cloacae Gram-negative Enterococcus Enterococcus faecalis Gram-positive Enterococcus faecium Escherichia Escherichia coli Gram-negative Francisella Francisella tularensis Gram-negative Haemophilus Haemophilus influenzae Gram-negative Helicobacter Helicobacter pylori Gram-negative Klebsiella Klebsiella oxytoca Gram-negative Klebsiella pneumoniae Legionella Legionella pneumophila Gram-negative Leptospira Leptospira interrogans Gram-negative Listeria Listeria monocytogenes Gram-positive Moraxella Moraxella catarrhalis Gram-negative Mycobacteriae Mycobacterium tuberculosis Gram-indeterminate Neisseria Neisseria gonorrhoeae Gram-negative Neisseria meningitidis Proteus Proteus vulgaris Gram-negative Pseudomonas Pseudomonas aeruginosa Gram-negative Rickettsia Rickettsia rickettsii Gram-negative Salmonella Salmonella typhi Gram-negative Salmonella typhimurium Shigella Shigella sonnei Gram-negative Staphylococcus Staphylococcus aureus Gram-positive Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus Streptococcus agalactiae Gram-positive Streptococcus pneumoniae Streptococcus pyogenes Treponema Treponema pallidum Gram-negative Vibrio Vibrio cholerae Gram-negative Yersinia Yersinia pestis Gram-negative Yersinia enterocolitica Yersinia pseudotuberculosis

The bacterial infection prevented and/or treated by compounds of the present invention may be infection by one or more Gram-positive bacteria. Furthermore, the compounds of the present invention may be selective for one or more Gram-positive bacteria over Gram-negative bacteria. Thus, compounds of the present invention may show no significant inhibition of growth of Gram-negative bacteria.

The bacterial infection prevented and/or treated by compounds of the present invention may be infection by one or more Gram-negative bacteria. Furthermore, the compounds of the present invention may be selective for one or more Gram-negative bacteria over Gram-positive bacteria. Thus, compounds of the present invention may show no significant inhibition of growth of Gram-positive bacteria.

Furthermore, the compounds of the present invention may inhibit the growth of both Gram-positive bacteria and Gram-negative bacteria.

Therapeutic index is the ratio of the dose that produces growth inhibition in 50% of CHO or HepG22 cells divided by the dose where 50% of S. aureus growth is inhibited. In some embodiments, compounds have a therapeutic index of greater than 1. In other embodiments, compounds have a therapeutic index of greater than 4. In other embodiments, compounds have a therapeutic index of greater than 8.

Representative examples of Gram-positive bacteria include Staphylococcus (e.g. S. aureus, S. epidermis), Enterococci (e.g. E. faecium, E. faecalis), Clostridia (e.g. C. difficile), Propionibacteria (e.g. P. acnes) and Streptococcus.

Bacterial infections in animals are, for example, described in “Pathogenesis of Bacterial Infections in Animals”, edited by Carlton L. Gyles, John F. Prescott, J. Glenn Songer, and Charles O. Thoen, published by Wiley-Blackwell (Fourth edition, 2010—ISBN 978-0-8138-1237-3), which is hereby incorporated by reference. Many are the same as listed above for humans.

Combinations

Treatments as described herein may be in combination with one or more know antibiotics, examples of which are described below:

(a) Aminoglyosides: Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin; Spectinomycin; (b) Ansamycins: Geldanamycin, Herbimycin, Rifaximin; (c) Carbacephem: Loracarbef; (d) Cabapenems: Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem;

(e) 1^(st) generation Cephlasporins: Cefadroxil, Cefazolin, Cefalotin or Cefalothin, Cefalexin; (f) 2^(nd) generation Cephlasporins: Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime; (g) 3^(rd) generation Cephlasporins: Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone; (h) 4^(th) generation Cephlasporins: Cefepime; (i) 5^(th) generation Cephlasporins: Ceftaroline fosamil, Ceftobiprole, Ceftolozane-tazobactam, Ceftaroline;

(j) Glycopeptides: Teicoplanin, Vancomycin, Telavancin, Dalbavancin, Oritavancin; (k) Lincosamides: Clindamycin, Lincomycin (l) Lipopeptide: Daptomycin (m) Macrolides: Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spiramycin, Rifabutin; Fidaxomicin; (n) Monobactams: Aztreonam; (o) Nitrofurans: Furazolidone, Nitrofurantoin;

(p) Oxazolidonones: Linezolid, Posizolid, Radezolid, Torezolid, Tedizolid, Tedizolid phosphate;

(q) Penicillins: Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin;

(r) Polypeptides: Bacitracin, Colistin, Polymyxin B, Polymyxin E (colistin); (s) Quinolones: Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin; (t) Sulfonamides: Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole, Sulfonamidochrysoidine;

(u) Tetracylines: Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline;

(v) Antibodies: bezlotoxumab; (w) Non-β-lactam β-lactamase inhibitors: avibactam;

(x) Quinolines: Bedaquiline; and

(y) Combinations: ceftazidime-avibactam, colistin-ceftazidime, colistin-rifabutin.

General Experimental

The invention also provides a process for the preparation of a compound of formula I:

which comprises reacting a compound of general formula II:

with chloro(trialkyl phosphine) gold(I) complexes of general formula III:

Isomers, Salts and Solvates Isomers

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specifically excluded from the term “isomers”, as used herein, are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, —OCH₃, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, —CH₂OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C₁₋₇alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹H, ²H (D), and ³H (T); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; Au may be in any isotopic forms, including ¹⁹⁷Au and ¹⁹⁵Au; S may be in any isotopic forms, including ³²S, ³³S, ³⁴S and ³⁶S; P may be in any isotopic forms, including ³¹P, ³³P and ³²P; and the like.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

Regioisomers

In some cases, the structural assignments for compounds described herein may be unconfirmed due to regioisomerism. When a reactant exists in multiple interchangeable tautomeric forms, the product may be one of a number of regioisomers (each regioisomer resulting from the reaction of a different tautomeric form), or a mixture of these forms. For example, the substituted pyrazole compound below exists in the tautomeric forms (A) and (B) shown:

where R′ represents a group that is not H. When this substituted pyrazole compound reacts with a gold(I) phosphine chloride reactant Cl—Au═PR₃, reaction may occur with either tautomer, producing the following two distinct regioisomeric products (A′) and (B′):

It is possible that these may interconvert in solution (as described in Nomiya, 1998)—any analytical approach used may indicate only one of the possible regioisomers, although the actual product formed may more correctly be assigned as (A′), (B′) or a mixture of the two.

Thus, when a structure is assigned herein as a compound which could exist as multiple regioisomers due to reaction of a gold(I) phosphine chloride with a reactant which exists in multiple interchangeable tautomeric forms, the skilled person will understand that the actual product may in fact be one or more of the regioisomers, and the disclosure of such compounds herein extends to all such regioisomers individually and as mixtures in any relative amount.

The specific compounds described herein which may exist as multiple regioisomers for this reason are indicated below.

Salts

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., —COOH may be —COO⁻), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may be cationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound also include salt forms thereof.

Solvates

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term “solvate” is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

Unless otherwise specified, a reference to a particular compound also include solvate forms thereof.

The Subject/Patient

The subject/patient may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development, for example, a foetus. In one preferred embodiment, the subject/patient is a human.

Dosage and Formulation

The dosage administered to a patient will normally be determined by the prescribing physician and will generally vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the proposed route of administration. However, in most instances, an effective therapeutic daily dosage will be in the range of from about 0.05 mg/kg to about 100 mg/kg of body weight and, preferably, of from 0.05 mg/kg to about 5 mg/kg of body weight administered in single or divided doses. In some cases, however, it may be necessary to use dosages outside these limits.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations, both for veterinary and for human medical use, of the present invention comprise a compound of formula (I) in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Conveniently, unit doses of a formulation contain between 0.1 mg and 1 g of the active ingredient. Preferably, the formulation is suitable for administration from one to six, such as two to four, times per day. For topical administration, the active ingredient preferably comprises from 1% to 2% by weight of the formulation but the active ingredient may comprise as much as 10% w/w. Formulations suitable for nasal or buccal administration, such as the self-propelling powder-dispensing formulations described hereinafter, may comprise 0.1 to 20% w/w, for example about 2% w/w of active ingredient.

The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, vaginal, intraperitoneal, intramuscular and intravenous), intra-articular, topical, nasal or buccal administration. The toxicity of certain of the compounds in accordance with the present invention will preclude their administration by systemic routes, and in those, and other, cases opthalmic, topical or buccal administration, and in particular topical administration, is preferred for the treatment of local infection.

Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary or paste. For such formulations, a range of dilutions of the active ingredient in the vehicle is suitable, such as from 1% to 99%, preferably 5% to 50% and more preferably 10% to 25% dilution.

Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration comprise a solution, suspension or emulsion, as described above, conveniently a sterile aqueous preparation of the active ingredient that is preferably isotonic with the blood of the recipient.

Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient, which may be in a microcrystalline form, for example, in the form of an aqueous microcrystalline suspension or as a micellar dispersion or suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient particularly for both intra-articular and ophthalmic administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions or applications; oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. For example, for ophthalmic administration, the active ingredient may be presented in the form of aqueous eye drops, as for example, a 0.1-1.0% solution.

Drops according to the present invention may comprise sterile aqueous or oily solutions. Preservatives, bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric salts (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Lotions according to the present invention include those suitable for application to the eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide or preservative prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol, or a softener or moisturiser such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient in a base for external application. The base may comprise one or more of a hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil such as a vegetable oil, eg almond, corn, arachis, castor or olive oil; wool fat or its derivatives; or a fatty acid ester of a fatty acid together with an alcohol such as propylene glycol or macrogols. The formulation may also comprise a suitable surface-active agent, such as an anionic, cationic or non-ionic surfactant such as a glycol or polyoxyethylene derivatives thereof. Suspending agents such as natural gums may be incorporated, optionally with other inorganic materials, such as silicaceous silicas, and other ingredients such as lanolin.

Formulations suitable for administration to the nose or buccal cavity include those suitable for inhalation or insufflation, and include powder, self-propelling and spray formulations such as aerosols and atomisers. The formulations, when dispersed, preferably have a particle size in the range of 10 to 200 μm.

Such formulations may be in the form of a finely comminuted powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations, where the active ingredient, as a finely comminuted powder, may comprise up to 99.9% w/w of the formulation.

Self-propelling powder-dispensing formulations preferably comprise dispersed particles of solid active ingredient, and a liquid propellant having a boiling point of below 18° C. at atmospheric pressure. Generally, the propellant constitutes 50 to 99.9% w/w of the formulation whilst the active ingredient constitutes 0.1 to 20% w/w. for example, about 2% w/w, of the formulation.

The pharmaceutically acceptable carrier in such self-propelling formulations may include other constituents in addition to the propellant, in particular a surfactant or a solid diluent or both. Especially valuable are liquid non-ionic surfactants and solid anionic surfactants or mixtures thereof. The liquid non-ionic surfactant may constitute from 0.01 up to 20% w/w of the formulation, though preferably it constitutes below 1% w/w of the formulation. The solid anionic surfactants may constitute from 0.01 up to 20% w/w of the formulation, though preferably below 1% w/w of the composition.

Formulations of the present invention may also be in the form of a self-propelling formulation wherein the active ingredient is present in solution. Such self-propelling formulations may comprise the active ingredient, propellant and co-solvent, and advantageously an antioxidant stabiliser. Suitable co-solvents are lower alkyl alcohols and mixtures thereof. The co-solvent may constitute 5 to 40% w/w of the formulation, though preferably less than 20% w/w of the formulation. Antioxidant stabilisers may be incorporated in such solution-formulations to inhibit deterioration of the active ingredient and are conveniently alkali metal ascorbates or bisulphites. They are preferably present in an amount of up to 0.25% w/w of the formulation.

Formulations of the present invention may also be in the form of an aqueous or dilute alcoholic solution, optionally a sterile solution, of the active ingredient for use in a nebuliser or atomiser, wherein an accelerated air stream is used to produce a fine mist consisting of small droplets of the solution.

In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives eg methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like. A particularly preferred carrier or diluent for use in the formulations of this invention is a lower alkyl ester of a C₁₈ to C₂₄ mono-unsaturated fatty acid, such as oleic acid, for example ethyl oleate. Other suitable carriers or diluents include capric or caprylic esters or triglycerides, or mixtures thereof, such as those caprylic/capric triglycerides sold under the trade name Miglyol, eg Miglyol 810.

Embodiments of the invention will now be described by way of example only.

EXAMPLES Preparative HPLC Methods

Reverse Phase Preparative HPLC-MS: Mass-directed purification by preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18 (2) 5 μm, 100×21.2 mm).

Generic Acidic Conditions:

A=water+0.1% formic acid; B=MeOH+0.1% formic acid; 20° C.; % B: 0.0 min Initial between 2% and 50%, 0.1 min % as per Initial, 7.0 min between 40% and 95%, 9.0 min 95%, 10.0 min 95%, 10.1 min back to Initial %; 12.0 min Initial %; 20.0 mL/min.

Generic Basic Conditions:

A=water pH 9 (Ammonium Bicarbonate 10 mM); B=MeOH; 20° C.; % B: 0.0 min Initial between 2% and 50%, 0.1 min % as per Initial, 7.0 min between 40% and 95%, 9.0 min 95%, 10.0 min 95%, 10.1 min back to Initial %; 12.0 min Initial %; 20.0 mL/min.

NMR was also used to characterise final compounds. NMR spectra were obtained Bruker Advance 400, Bruker DRX 400 or Jeol 400 ECS at room temperature unless otherwise stated. 1H NMR spectra are reported in ppm and referenced to either tetramethylsilane (0.00 ppm), DMSO-d6 (2.50 ppm), CDCl₃ (7.26 ppm) or CD₃OD (3.31 ppm).

Abbreviations Used

For the examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings.

-   ° C. Degrees Centigrade -   aq. Aqueous -   br Broad -   d Doublet -   DABCO 1,4-Diazabicyclo[2.2.2]octane -   DavePhos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl -   DCM Dichloromethane -   DIPEA N,N-Diisopropylethylamine -   DMF Dimethylformamide -   DMSO Dimethyl sulfoxide -   Et Ethyl -   EtOAc Ethyl acetate -   EtOH Ethanol -   Et₂O Diethyl ether -   FA Formic acid -   g Gram -   h Hour(s) -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium     hexafluorophosphate -   ^(i)Pr Isopropyl -   J Coupling constant -   LC-MS Liquid chromatography-mass spectrometry -   LiHMDS Lithium bis(trimethylsilyl)amide -   Me Methyl -   MeCN Acetonitrile -   MeOH Methanol -   mg Milligram -   min Minute(s) -   mL Milliliter -   mmol Millimole -   NaOMe Sodium methoxide -   O/N Overnight -   ppm Parts per million -   ppt Precipitate -   q Quartet -   quint Quintet -   rt Room temperature -   s Singlet -   sext sextet -   TEA Triethylamine -   THF Tetrahydrofuran -   TLC Thin layer chromatography -   t Triplet -   WIPE Water/isopropanol/Ethyl acetate (1:2:9)

Chemical Synthesis

Several of the requisite gold(I) phosphine chloride complexes III, necessary for coupling with precursors II, required synthesis from commercial starting materials. Other precursors used were commercially available.

Dimethylethylphosphine gold(I) chloride I-3

(a) Dimethylphosphine borane I-1

Cerium(III) chloride (25 g, 101.4 mmol) was suspended in THF (100 mL) and stirred at rt for 1 h. Sodium borohydride (3.8 g, 101.4 mmol) was then added and the suspension stirred at rt for a further 1 h. The reaction was cooled to 0° C. at which point dimethylphosphine oxide (2.6 g, 33.8 mmol) was added dropwise followed by lithium aluminium hydride (1M in THF, 40.7 mL, 40.7 mmol) also dropwise. The reaction was stirred at rt O/N before diluting with toluene (50 mL) then quenching with water (25 mL) and aqueous HCl (6N, 25 mL). The suspension was filtered through celite and the layers separated. The aqueous phase was extracted with DCM (3×40 mL) and the combined organic extracts washed with brine (1×40 mL) and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a yellow oil which was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil column eluting with isohexane to 20% EtOAc/isohexane to provide the title compound as a colourless oil (1.49 g, 19.6 mmol, 58%).

(b) Dimethylethylphosphine borane I-2

Dimethylphosphine borane I-1 (100 mg, 1.3 mmol) was dissolved in THF (3 mL) and the colourless solution cooled to 0° C. NaH (60% dispersion in mineral oil, 53 mg, 1.3 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 10 min then cooled back down to 0° C. whereupon iodoethane (0.12 mL, 1.4 mmol) was added in one portion. When TLC had indicated completion of the reaction, water (10 mL) and Et₂O (10 mL) were added and the phases separated. The aqueous phase was extracted with Et₂O (2×15 mL) and the combined organic extracts washed with brine (1×20 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material as a colourless gum. Purification by column chromatography (Biotage Isolera Four, 10 g KP-Sil column eluting with a gradient of isohexane to 20% EtOAc/isohexane provided the title compound as a white solid (122 mg, 1.1 mmol, 90%).

(c) Dimethylethylphosphine gold(I) chloride I-3

Dimethylethylphosphine borane I-2 (225 mg, 2.0 mmol) was dissolved in THF (5 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (640 mg, 6.0 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100° C. and stirred at this temperature for 4 h before cooling in an ice bath and adding a solution of chloro(tetrahydrothiophene)gold(I) (640 mg, 2.0 mmol) in DCM (5 mL). After stirring at rt O/N the reaction was diluted with DCM (10 mL) and water (10 mL) and the phases separated. The aqueous phase was extracted with DCM (2×20 mL) and the combined organic extracts washed with brine (20 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a brown oil which was purified by column chromatography (Biotage SP1, 25 g KP-Sil eluting with 25% EtOAc/isohexane to 60% EtOAc/isohexane to provide the title compound as a white solid (265 mg, 0.82 mmol, 41%).

1-Methylphospholane gold(I) chloride I-5

(a) 1-Methylphospholaneborane I-4

The bis-Grignard reagent was prepared by treating magnesium (1.0 g, 0.04 mol) with 1,4-dibromobutane (4.3 g, 20 mmol) in dry THF (50 mL) at 65° C. for 3 h. The reaction mixture was cooled to 0° C. before adding a cooled (10° C.) solution of dichloromethyl phosphine (2.3 g, 20 mmol) in dry THF (25 mL) dropwise maintaining a temperature of 10° C. The mixture was stirred O/N at rt. Borane-THF complex (1.0M in THF, 20 mL, 20 mmol) was added dropwise and the reaction mixture stirred for additional 4 h. The reaction mixture was poured onto a mixture of ice (200 g) and aqueous HCl (2M, 100 mL) with vigorous stirring. The aqueous phase was extracted with DCM (3×100 mL) and the combined organic extracts dried over MgSO₄. Concentration in vacuo gave the crude product as a yellow oil which was purified by flash column chromatography (Biotage SP1, 50 g KP-Sil column, eluting with isohexane to DCM) to provide the title compound as a colourless oil (700 mg, 6.0 mmol, 30%).

(b) 1-Methylphospholane gold(I) chloride I-5

Procedure similar to that described for dimethylethylphosphine gold(I) chloride I-3 starting from 1-methylphospholaneborane I-4 (116 mg, 1.0 mmol) to provide the title compound as an off-white solid (200 mg, 0.6 mmol, 60%).

Diethylmethylphosphine gold(I) chloride I-7

(a) Diethylmethylphosphine borane I-6

To a cold (0° C.) solution of diethylchlorophosphine (1.0 g, 8.0 mmol) in THF (20 mL) under an inert atmosphere was slowly added methylmagnesium chloride (3M in THF, 2.7 mL, 8.1 mmol). After warming to rt and being stirred for 4 h, the reaction was cooled to 0° C. prior to the addition of borane-THF complex (1M in THF, 8 mL, 8.0 mmol). The reaction mixture was allowed to warm up to rt O/N, then was diluted with Et₂O (30 mL) and water (20 mL). The phases were separated and the organic layer was washed with water (2×10 mL) and brine (10 mL) before being dried over MgSO₄ and concentrated in vacuo to provide the title compound as a colourless oil (388 mg, 3.2 mmol, 40%).

(b) Diethylmethylphosphine gold(I) chloride I-7

Procedure similar to that described for dimethylethylphosphine gold(I) chloride I-3 starting from diethylmethylphosphine borane I-6 (385 mg, 3.2 mmol) to provide the title compound as a white solid (475 mg, 1.4 mmol, 44%).

4-Methyl-[1,4]oxaphosphinane gold(I) chloride I-9

(a) 4-Methyl-[1,4]oxaphosphinaneborane I-8

To a solution of diethyl methylphosphonate (1.5 g, 10.0 mmol) in dry THF (30 mL) was added lithium aluminium hydride (1M in THF, 15 mL, 15.0 mmol) at 00° C., and the mixture allowed to warm to rt and stirred for 4 h. The reaction mixture was cooled to 00° C. whereupon BuLi (1.6M in hexanes, 12.5 mL, 20 mmol) was added over 5 min and stirring continued at 00° C. for 45 min. 1-Bromo-2-(2-bromoethoxy)ethane (2.3 g, 10 mmol) was then added in one portion and the reaction mixture stirred for further 4 h. Borane-THF complex (1M in THF, 20 mL, 20 mmol) was added and the reaction mixture stirred at rt for an additional 72 h before being diluted with water (60 mL) and 2M HCl (aq., 160 mL) with vigorous stirring. The aqueous phase was extracted with DCM and the combined organic extracts dried over MgSO₄. Concentration in vacuo gave the crude product which was purified by flash column chromatography (Biotage SP1, 25 g KP-Sil column, eluting with isohexane to EtOAc) to provide the title compound as a colourless oil (220 mg, 1.7 mmol, 17%).

(b) 4-Methyl-[1,4]oxaphosphinane gold(I) chloride I-9

Procedure similar to that described for dimethylethylphosphine gold(I) chloride I-3 starting from 4-methyl-[1,4]oxaphosphinaneborane I-8 (220 mg, 1.7 mmol) to provide the title compound as an off-white solid (186 mg, 0.5 mmol, 32%).

A number of the requisite precursors II, necessary for coupling with chloro(trialkyl phosphine) gold(I) complexes III, required synthesis from commercial starting materials. Other precursors used were commercially available.

7-Morpholin-4-yl-4H-benzo[1,4]oxazin-3-one I-10

7-Bromo-4H-benzo[1,4]oxazin-3-one (300 mg, 1.3 mmol), morpholine (140 μL, 1.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.9 mmg, 0.013 mmol) and DavePhos (15.3 mg, 0.039 mmol) were combined in THF (5 mL). The reaction was degassed with nitrogen and LiHMDS (3.3 mL, 3.3 mmol) was added and the reaction heated under nitrogen at 70° C. O/N. The reaction mixture was cooled to rt, diluted with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO₄), filtered and concentrated in vacuo to afford a brown solid. The residue was purified by column chromatography (Biotage Isolera Four, 25 g, KP-Sil column, eluting with isohexane to EtOAc) to afford the title compound as a brown solid (125 mg, 0.53 mmol, 41%).

1H-Indazole-7-carboxylic acid dimethylamide I-11 and 1H-indazole-7-carboxylic acid diethylamide I-12

(a) 1H-Indazole-7-carboxylic acid dimethylamide I-11

1H-Indazole-7-carboxylic acid (100 mg, 0.62 mmol) was suspended in anhydrous DCM (10 mL). DIPEA (430 μL, 2.47 mmol) was added followed by HATU (281 mg, 0.74 mmol) and the reaction was stirred at rt for 20 min. Dimethylamine hydrochloride (100 mg, 1.23 mmol) was added and the reaction stirred at rt O/N. Additional dimethylamine hydrochloride (100 mg, 1.23 mmol), DIPEA (1 mL, 5.74 mmol) and HATU (281 mg, 0.74 mmol) were added and the reaction stirred for a further 18 h. The reaction was diluted with DCM and washed with water and saturated aqueous sodium hydrogen carbonate. The organic fraction was dried and concentrated in vacuo. Initial purification by column chromatography (Biotage Isolera Four, 10 g, KP-Sil column, eluting with isohexane to EtOAc) afforded impure title compound. Final purification by preparative HPLC (acidic conditions) afforded the title compound as a white solid, (43 mg, 0.23 mmol, 37%). An alternative procedure can be employed using 1H-indazole-7-carboxylic acid (198 mg, 0.62 mmol) and TEA (6.1 mmol) as base. The crude product was purified directly by preparative HPLC (basic conditions) to afford the title compound as a white solid, (108 mg, 0.57 mmol, 47%).

(b) 1H-Indazole-7-carboxylic acid diethylamide I-12

Procedure similar to that described for 1H-indazole-7-carboxylic acid dimethylamide I-11 starting from diethylamine (191 μL, 1.85 mmol) to provide the title compound as a white solid (93 mg, 0.43 mmol, 49%).

1H-Benzoimidazole-2-carboxylic acid dimethylamide I-13 and 1H-benzoimidazole-2-carboxylic acid methoxy-methyl-amide I-14

(a) 1H-Benzoimidazole-2-carboxylic acid dimethylamide I-13

1H-Benzoimidazole-2-carboxylic acid (150 mg, 0.93 mmol) was suspended in anhydrous DMF (10 mL). DIPEA (480 μL, 2.76 mmol) was added followed by HATU (530 mg, 1.39 mmol) and the reaction was stirred at rt for 20 min. Dimethylamine hydrochloride (157 mg, 1.86 mmol) was added and the reaction stirred at rt O/N. The reaction was diluted with saturated aqueous sodium hydrogen carbonate and extracted with DCM. The organic fraction was dried and concentrated in vacuo. Purification by column chromatography (Biotage Isolera Four, 25 g KP-Sil column, eluting with isohexane to EtOAc) afforded impure title compound as a white solid, (80 mg, 0.42 mmol, 46%).

(b) 1H-benzoimidazole-2-carboxylic acid methoxy-methyl-amide I-14

Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from N-methyl,O-methyl hydroxylamine hydrochloride (181 mg, 1.86 mmol) to provide the title compound as an off-white solid (103 mg, 0.5 mmol, 54%).

1H-Imidazole-2-carboxylic acid dimethylamide I-15

Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from imidazole-2-carboxylic acid (218 mg, 2.67 mmol) to provide the title compound as a yellow oil (256 mg, 1.83 mmol, 54%).

1H-Indole-7-carboxylic acid dimethylamide I-16 and 1H-indole-7-carboxylic acid methoxy-methylamide I-17

(a) 1H-Indole-7-carboxylic acid dimethylamide I-16

Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from 7-indole carboxylic acid (200 mg, 1.24 mmol) to provide the title compound as a white solid (194 mg, 1.03 mmol, 83%).

(b) 1H-Indole-7-carboxylic acid methoxy-methylamide I-17

Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from 7-indole carboxylic acid (200 mg, 1.24 mmol) and N-methyl,O-methyl hydroxylamine hydrochloride (240 mg, 2.45 mmol) to provide the title compound as a white solid (262 mg, 1.28 mmol, 100%).

Compounds of the formula I were synthesised via the coupling of gold(I) phosphine chloride complexes of formula III with nitrogen containing derivatives of general formula II:

Example 1

Method A:

To a stirred suspension of the appropriate nitrogen derivative II (0.16 mmol) and chlorophosphine gold(I) compound III (0.16 mmol) in MeOH (2 mL) was added dropwise NaOMe (0.5 M in MeOH, 0.18 mmol). The reaction was stirred at rt for 16 h before concentrating in vacuo to give a solid residue which was suspended in DCM (2 mL) and filtered. The filtrate was concentrated in vacuo giving an oily residue which after trituration with Et₂O (×3) and drying under high vacuum for 16 h, provided the title compound I.

Method B:

As Method A, except NaOH was used instead of NaOMe and EtOH instead of MeOH. The reaction was stirred at 0° C. for 75 min before the reaction mixture was concentrated in vacuo, re-suspended in water (10 mL) and extracted with DCM (3×10 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and concentrated in vacuo to give a residue which was triturated with Et₂O (×3) to provide the title compound I.

Method C:

As Method A, except NaOH was used instead of NaOMe.

Method D:

As Method A except 2 equivalents of chlorophosphine gold(I) compound III and 2.2 equivalents of NaOMe were used.

Method E:

As Method A except the reaction mixture was heated at 50° C. for 18 h.

Method F:

As Method A except workup and isolation as Method B.

Method G:

As Method A except the order of addition of reagents was changed such that the base was added prior to addition of chlorophosphine gold(I) compound III.

Method H:

To a stirred solution of the appropriate nitrogen derivative II (0.1 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.1 mmol). The reaction mixture was stirred at rt for 15 min whereupon chlorophosphine gold(I) compound III (0.1 mmol) was added. The reaction mixture was stirred at rt for 18 h before concentrating in vacuo. The resulting residue was suspended in DCM (2 mL) and filtered. The filtrate was concentrated in vacuo, triturated with Et₂O and isohexane, and dried under high vacuum for 16 h to provide the title compound I.

Method I:

As Method A except 2 equivalents of NaOMe were used and after 16 h, the reaction was concentrated in vacuo to afford the title compound I.

Method J:

As Method A except after 16 h, the reaction was concentration in vacuo, the resulting solid was triturated with DCM and then dissolved in MeOH. The solution was filtered, concentrated in vacuo and the resulting solid triturated further with Et₂O and dried under high vacuum to provide the title compound I.

Method K:

To a stirred solution of the appropriate nitrogen derivative II (0.3 mmol) in EtOH (3 mL) was added aqueous K₂CO₃ (10% w/v, 1 mL) followed by chlorophosphine gold(I) compound III (0.3 mmol). The reaction mixture was stirred at RT for 18 h before it was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the title compound I.

For compounds 94, 95, 96, and 98 the reaction was run in the dark by covering the reaction vessel in foil.

The solvent (or combination of solvents) used for trituration and isolation of target compounds I can be selected from the following: MeOH, EtOH, Et₂O, EtOAc, isohexane, pentane or DCM.

Some of the compounds were prepared using methods in which minor modifications to the general methods were made; specifically, these methods involved small changes to the stoichiometry of reagents (1-2.2 equivalents), duration of reaction (1-86 h) and volume of solvent (2-6 mL). In some cases reactions were purged with nitrogen.

The following compounds were made using these methods:

TABLE 1 Compound Analytical Data Structure Number Method Physical appearance/Yield

 1 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.84 (2H, s), 3.56 (2H, t, J = 4.7 Hz), 3.36 (2H, t, J = 4.7 Hz), 1.58 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.46 (s). Grey solid; 55 mg, 90%

 2 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.29 (2H, t, J = 5.6 Hz), 2.03 (2H, t, J = 6.8 Hz), 1.47-1.65 (m, 13H). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.57 (s). White solid; 91 mg, 71%

 3 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.84 (2H, s), 3.56 (2H, t, J = 4.5 Hz), 3.37 (2H, t, J = 4.5 Hz), 1.88 (6H, dq, J = 10.4, 7.6 Hz), 1.11 (9H, dt, J = 18.7, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −30.52 (s). Grey solid; 32 mg, 48%

 4 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.29 (2 H, dq J = 7.2, 3.6 Hz), 1.92 (3H, s), 1.59 (9H, d, J = 11.4 Hz), 1.04 (3H, t, J = 7.2 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.70 (s). Dark grey solid; 35 mg, 60%

 5 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.30 (2H, t, J = 7.6 Hz), 3.11 (2H, t, J = 7.6 Hz), 2.51 (3H, s), 1.57 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.08 (s) Grey solid; 51 mg, 85%

 6 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.53-7.48 (2H, m), 7.24-7.18 (2H, m), 6.82 (1H, tt, J = 7.3, 1.1 Hz), 3.70 (2H, t, J = 7.6 Hz), 3.51 (2H, t, J = 7.6 Hz), 1.60 (9H, d, J = 1.14 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.11 (s) White solid; 62 mg, 88%

 7 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 2.43 (4H, s), 1.62 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.80 (s) Off-white solid; 51 mg, 85%

 8 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 4.11 (4H, s), 1.63 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.24 (s) Brown solid; 36 mg, 57%

 9 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 4.09 (2H, t, J = 7.8 Hz), 3.49 (2H, t, J = 7.8 Hz), 1.59 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.21 (s). White solid; 57 mg, 98%

 10 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.70-7.64 (4H, m), 1.67 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.61 (s) White solid; 53 mg, 74%

 11 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.71-7.62 (4H, m), 1.98 (6H, dq, J = 18.9, 7.6 Hz), 1.15 (9H, dt, J = 18.9, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 31.65 (s) Grey solid; 20 mg, 25%

 12 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.29 (1H, dd, J = 7.8, 1.8 Hz), 6.87-6.81 (2H, m), 6.74 (1H, m), 4.36 (2H, s), 1.66 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.47 (s) White solid; 58 mg, 84%

 13 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.31 (1H, m), 7.14 (1H, ddd, J = 8.8, 6.6, 2.3 Hz), 6.14 (1H, dm, J = 9.1 Hz), 6.01 (1H, tt, J = 6.3, 1.3 Hz), 1.63 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.29 (s). Brown solid; 43 mg, 72%

 14 A ¹H-NMR (400 MHz, CDCl₃): δ ppm 2.51 (4H, t, J = 6.7 Hz), 1.92 (2H, quint, J = 6.6 Hz), 1.61 (9H, d, J = 11.1 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm −11.40 (s) Brown solid; 47 mg, 76%

 15 B ¹H-NMR (400 MHz, CDCl₃): δ ppm 4.02 (1H, t, J = 8.1 Hz), 3.68 (1H, dt, J = 11.4, 7.1 Hz), 3.13 (1H, m), 2.14 (1H, m), 2.07-1.88 (2H, m), 1.76 (1H, m), 1.61 (9H, d, J = 11.1 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm −11.25 (s) Pink solid; 27 mg, 28%

 16 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.51 (2H, dd, J = 8.6, 1.0 Hz), 7.34 (2H, dd, J = 8.6, 7.6 Hz), 7.06 (1H, tt, J = 7.6, 1.0 Hz), 4.66 (1H, q, J = 6.8 Hz), 1.66 (9H, d, J = 11.6 Hz), 1.25 (3H, d, J = 6.8 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.10 (s) White solid; 73 mg, 97%

 17 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 2.68 (3H, s), 1.62 (9H, d, J = 11.6 Hz), 1.18 (6H, s). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.10 (s) Off-white solid; 62 mg, 93%

 18 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.98 (2H, t, J = 5.7 Hz), 3.32 (2H, t, J = 5.7 Hz), 1.70 (2H, quint, J = 5.7 Hz), 1.57 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.46 (s) Brown solid; 45 mg, 75%

 19 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 2.70 (3H, s), 1.81-1.67 (8H, m), 1.62 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −10.12 (s). White solid; 60 mg, 85%

 20 E ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.53 (1H, dt, J = 7.3, 1.0 Hz), 7.45-7.42 (2H, m), 7.37 (1H, m), 4.35 (2H, s), 1.64 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.58 (s). Off-white solid; 45 mg, 69%

 21 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 2.82 (3H, d, J = 2.2 Hz), 2.62 (3H, s), 1.59 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.70 (s) Grey solid; 61 mg, 98%

 22 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.71 (2H, s), 2.75 (3H, s), 1.62 (9H, d, J = 11.6 Hz). ³¹P-NMR(162 MHz, DMSO- d6): δ ppm −9.99 (s) White solid; 52 mg, 83%

 23 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.61-7.57 (2H, m), 7.34-7.28 (2H, m), 7.01 (1H, tt, J = 7.3, 1.0 Hz), 4.26 (2H, s), 1.65 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.93 (s) White solid; 53 mg, 73%

 24 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.77-7.72 (2H, m), 7.52-7.48 (3H, m), 2.66 (3H, d, J = 2.0 Hz), 1.62 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.61 (s) Grey solid; 19 mg, 26%

 25 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.77-7.73 (2H, m), 7.38-7.32 (2H, m), 7.09 (1H, tt, J = 7.6, 1.0 Hz), 6.77 (1H, dd, J = 2.8, 1.3 Hz), 6.29 (1H, dd, J = 2.8, 0.8 Hz), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.33 (s) White solid; 43 mg, 61%

 26 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.42-7.37 (2H, m), 6.83-6.78 (2H, m), 3.68 (3H, s), 3.68-3.62 (2H, m), 3.52-3.46 (2H, m), 1.59 (9H d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.80 (s) Brown solid; 54 mg, 71%

 27 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.53-7.47 (2H, m), 7.08-7.01 (2H, m), 3.70- 3.65 (2H, m), 3.53-3.47 (2H, m), 1.59 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −9.91 (s) White solid; 51 mg, 68%

 28 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.32 (2H, t, J = 6.6 Hz), 2.76-2.70 (2H, m), 2.20-2.12 (2H, m), 1.59 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.73 (s) White solid; 47 mg, 73%

 29 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.39-3.33 (2H, m), 2.72-2.68 (2H, m), 1.98- 1.91 (2H, m), 1.58 (9H, d, J = 11.6 Hz), 1.49-1.42 (2H, m). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.24 (s) Off-white solid; 48 mg, 73%

 30 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 1.65 (9H, d, J = 11.9 Hz), 1.37 (6H, s). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.01 (s) Grey solid; 59 mg, 91%

 31 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.29 (2H, t, J = 6.6 Hz), 1.96-1.84 (4H, m), 1.57 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.28 (s) White solid; 51 mg, 88%

 32 F ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.84 (1H, dd, J = 5.0, 1.5 Hz), 8.09 (1H, dd, J = 7.6, 1.5 Hz), 7.64 (1H, dd, J = 7.6, 5.0 Hz), 1.68 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.40 (s) White solid; 43 mg, 63%

 33 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.45 (1H, app d, J = 7.3 Hz), 5.97 (1H, app d, J = 7.3 Hz), 1.64 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.17 (s) Brown solid; 32 mg, 53%

 34* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.76 (2H, br s), 1.89 (6H, dq, J = 10.1, 7.6 Hz), 1.23 (9H, dt, J = 18.7, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 27.19 (br s) Colourless oil; 120 mg, 100%

 35 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.65 (2H, br s), 6.39 (1H, t, J = 1.9 Hz), 1.86 (6H, dq, J = 10.1, 7.7 Hz), 1.23 (9H, dt, J = 18.7, 7.7 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm 30.41 (br s) Colourless oil; 122 mg, 100%

 36 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.45 (2H, brs), 6.19 (1H, t, J = 1.8 Hz), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.88 (s) White solid; 161 mg, 98%

 37* C ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.75 (2H, brs), 1.61 (9H, d, J = 11.1 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm −12.29 (s) Beige solid; 101 mg, 97%

 38* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.96 (2H, br s), 1.67 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.86 (s) White solid; 52 mg, 95%

 39* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.70 (1H, br s), 7.42 (1H, d, J = 8.3 Hz), 7.08 (1H br s), 6.66 (1H, d, J = 8.3 Hz), 3.75 (3H, s), 1.71 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.20 (s) Yellow solid; 54 mg, 79%

 40* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.74 (1H, brs), 1.71 (9H, d, J = 12.1 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.71 (s) White solid; 51 mg, 92%

 41 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.83 (2H, s), 1.65 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.45 (s) Off-white solid; 36 mg, 55%

 42* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.33 (1H, dd, J = 4.4, 2.8 Hz), 8.08 (1H, dd, J = 7.9, 1.5 Hz), 8.02 (1H, br s), 6.93 (1H, dd, J = 7.9, 4.4 Hz), 1.71 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.81 (s) Off-white solid; 46 mg, 73%

 43 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.22 (1H, br s), 6.87 (2H, br s,), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.16 (s) White solid; 49 mg, 86%

 44 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.80 (1H, br s), 7.56 (2H, dd, J = 5.8, 3.1 Hz), 7.00 (2H, dd, J = 5.8, 3.1 Hz), 1.71 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.26 (s) White solid; 62 mg, 95%

 45 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.43 (2H, br s), 6.91 (2H, br s), 2.48 (3H, s), 1.71 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −8.71 (s) Pale pink solid; 66 mg, 97%

 46* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 2.17 (6H, brs), 1.65 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.21 (s) White solid; 40 mg, 67%

 47 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 6.65 (2H, br s), 2.27 (3H, s), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.57 (s) White solid; 61 mg, 100%

 48 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.04 (2H, s), 1.68 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.69 (s) Grey solid; 61 mg, 92%

 49** A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.59 (1H, br s), 6.85 (1H, br s), 1.66 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −11.23 (s) White solid; 48 mg, 80%

 50* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.86 (1H, d, J = 1.0 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 2.3 Hz), 6.78 (1H, dd, J = 8.8, 2.3 Hz), 3.73 (3H, s), 1.69 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.17 (s) White solid; 42 mg, 62%

 51* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.19 (1H, d, J = 4.5 Hz), 8.00 (1H, s), 7.92 (1H, dd, J = 7.8, 1.3 Hz), 7.04 (1H, dd, J = 7.8, 4.5 Hz), 1.72 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.00 (s) Yellow solid; 59 mg, 94%

 52* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.34 (1H, dd, J = 4.5, 1.8 Hz), 8.08 (1H, ddd, J = 7.8, 1.8, 0.9 Hz), 8.03 (1H, d, J = 0.9 Hz), 6.94 (1H, dd, J = 7.8, 4.5 Hz), 2.01 (2H, dq, J = 11.4, 7.6 Hz), 1.70 (6H, d, J = 11.4 Hz), 1.91 (3H, dt, 20.2, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 3.01 (s) Brown oil; 34 mg, 54%

 53* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 9.00 (1H, s), 8.73 (1H, s), 8.17 (1H, br s), 1.73 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.73 (s) Beige solid; 51 mg, 80%

 54 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.13 (1H, dd, J = 4.5, 1.5 Hz), 7.79 (1H, app d, J = 8.1 Hz), 7.42 (1H, dd, J = 2.8, 0.8 Hz), 6.89 (1H, dd, J = 8.1, 4.5 Hz), 6.43 (1H, m), 1.69 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.17 (s) White solid; 45 mg, 71%

 55 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.05 (1H, dd, J = 4.7, 1.6 Hz), 7.81 (1H, ddd, J = 7.7, 1.6, 0.8 Hz), 7.28 (1H, d, J = 2.8 Hz), 6.83 (1H, dd, J = 7.7, 4.7 Hz), 6.29 (1H, dd, J = 2.8, 1.3 Hz), 1.69 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.01 (s) White solid; 40 mg, 63%

 56 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.74 (1H, m), 7.65 (1H, m), 7.36 (1H, dd, J = 2.5, 0.5 Hz), 7.09 (1H, ddd, J = 8.1, 6.8, 1.3 Hz), 7.00 (1H, ddd, J = 7.8, 6.8, 1.0 Hz), 6.51 (1H, m), 1.90 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.06 (s) Pale pink solid; 58 mg, 92%

 57 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.60 (1H, s), 7.09 (2H, s), 3.75 (6H, s), 1.71 (9H, d,J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.08 (s) Off-white solid; 66 mg, 90%

 58* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.39 (2H, m), 8.32 (1H, s), 1.72 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.54 (s) Off-white solid; 39 mg, 61%

 59* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.98 (1H, app d, J = 8.1 Hz), 7.75 (1H, app d, J = 8.3 Hz), 7.24 (1H, m), 7.12 (1H, m), 3.85 (3H, s), 1.73 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.04 (s) White solid; 30 mg, 41%

 60 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.39 (2H, s), 6.10 (1H, s), 1.95-1.86 (2H, m), 1.57 (6H, d, J = 10.6 Hz), 1.11 (3H, dt, J = 19.7, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 2.32 (s) Light brown solid; 36 mg, 57%

 61* A ¹H-NMR (400 MHz, CDCl₃): δ ppm 8.34 (1H, dd, J = 4.3, 1.5 Hz), 7.98 (1H, br s), 7.94 (1H, dd, J = 8.1, 1.5 Hz), 6.78 (1H, dd, J = 8.1, 1.5 Hz), 2.24-2.14 (2H, m,), 1.84-1.74 (6H, m), 1.63 (3H, d, J = 10.9 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm 10.74 (s) Light brown solid; 28 mg, 67%

 62* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.34 (1H, s), 7.31 (1H, m), 1.66 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.18 (s) White solid; 58 mg, 88%

 63 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.04 (1H, ddd, J = 6.8, 1.5. 0.5 Hz). 6.89 (1H, ddd, J = 6.8, 1.5, 0.5 Hz), 6.83 (1H, td, J = 6.8, 1.5 Hz), 6.80 (1H, td, J = 6.8, 1.5 Hz), 3.23 (3H, s), 1.69 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz. DMSO-d6): δ ppm −9.19 (s). Cream solid; 59 mg, 87%

 64 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.80 (1H, d, J = 7.6 Hz), 7.68 (1H, d, J = 7.8 Hz), 7.27-7.12 (2H, m), 1.75 (9H, d, J = 12.1 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.39 (s) Brown solid; 27 mg, 36%

 65* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.85 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.33 (1H, m), 7.20 (1H, m), 1.73 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.27 (s) White solid; 44 mg, 65%

 66* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 9.18 (1H, s), 8.76 (1H, s), 8.26 (1H, s), 1.72 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.07 (s) White solid; 42 mg, 66%

 67* A ¹H-NMR (400 MHz, CDCl₃): δ ppm 8.20 (1H, br s), 7.92 (1H, br s), 7.52 (1H, app d, J = 7.1 Hz), 7.00 (1H, app t, J = 7.6 Hz), 1.66 (9H, d, J = 11.1 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm −12.84 (s) Pale yellow solid; 39 mg, 52%

 68 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.73 (1H, d, J = 7.6 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.19 (1H, dd, J = 7.6, 7.1 Hz), 7.13 (1H, dd, J = 8.1, 7.1 Hz), 3.88 (3H, s), 1.74 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −10.96 (s) White solid; 23 mg, 32%

 69 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.33 (1H, s), 8.24 (2H, br s), 1.72 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −10.04 (s) Brown solid; 58 mg, 91%

 70 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 3.83 (2H, s), 3.55 (2H, t, J = 4.8 Hz), 3.35 (2H, t, J = 4.8 Hz), 1.87 (2H, dq, J = 10.8, 7.6 Hz), 1.54 (6H, d, J = 10.6 Hz), 1.10 (3H, dt, J = 19.9, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 3.1 (s) Brown oil; 42 mg. 74%

 71 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.49 (1H, dd, J = 8.3, 2.0 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.34 (1H, d, J = 2.0 Hz), 4.46 (2H, s), 3.78 (3H, s), 1.68 (9H, d, J = 12.0 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.51 (s) White solid; 69 mg, 89%

 72 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.83 (1H, dd, J = 5.1, 1.5 Hz), 7.17 (1H, ddd, J = 7.6, 1.5, 0.5 Hz), 6.76 (1H, dd, J = 7.6, 5.0 Hz), 4.46 (2H, s), 1.65 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.83 (s) Off-white solid; 40 mg, 59%

 73 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.14 (1H, m), 6.48-6.44 (2H, m), 4.31 (2H, s), 3.71-3.68 (4H, m), 2.97-2.94 (4H, m), 1.65 (9H, d, J = 11.2 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.46 (s) Off-white solid; 66 mg, 80%

 74 A ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.57 (2H, app d, J = 8.8 Hz), 6.64 (2H, app d, J = 8.8 Hz). 6.06 (1H, s), 5.50 (2H, s), 2.25 (3H, S), 1.68 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, CD₃OD): δ ppm −11.50 (s) Beige solid; 82 mg, 96%

 75 C ¹H-NMR (400 MHz, CD₃CN): δ ppm 5.20 (1H, br s), 3.64 (2H, s), 2.86 (3H, s), 1.59 (9H, d, J = 11.4 Hz). ³¹P-NMR(162 MHz, CD₃CN): δ ppm −9.61 (s) Cream solid; 56 mg, 90 %

 76 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.26 (1H, dd, J = 7.8, 1.5 Hz), 6.88-6.82 (2H, m), 6.78-6.72 (1H, m), 4.37 (2H, s), 2.05-1.90 (4H, m), 1.62 (3H, d, J = 10.9 Hz), 1.17 (6H, dt, J = 19.5, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 18.03 (s) Cream solid; 43 mg, 64%

 77 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.07 (2H, br s), 6.68 (2H, br s), 5.57 (2H, br s), 1.69 (9H,d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −8.52 (s) White solid; 55 mg, 84%

 78 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.73 (1H, s), 7.94 (1H, d, J = 5.6 Hz), 7.43 (1H, d, J = 5.6 Hz), 7.23 (1H, d, J = 2.5 Hz), 6.46 (1H, m), 1.70 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.30 (s) White solid; 26 mg, 41%

 79 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.85 (1H, s), 7.85 (1H, d, J = 5.4 Hz), 7.40 (1H, d, J = 5.4 Hz), 7.38 (1H, d, J = 2.4 Hz), 6.38 (1H, m), 1.71 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.34 (s) Pale orange solid; 32 mg, 51 %

 80 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.08 (1H, s), 7.06 (1H, s), 3.75 (3H, s), 1.67 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.97 (s) Pale pink solid; 60 mg, 93%.

 81 I ¹H-NMR (400 MHz. DMSO-d6): δ ppm 6.85 (2H, br s), 1.63 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −13.17 (s) White solid; 67 mg, 89%

 82 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.90 (2H, br s), 3.67 (3H, s), 1.65 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.43 (s) White solid; 61 mg. 95%

 83 I ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.56 (1H, br s), 7.49 (1H, br s), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.53 (s) White solid; 67 mg, 89%

 84* A ¹H-NMR (400 MHz. DMSO-d6): δ ppm 8.16 (1H, s), 7.95 (1H, d, J = 7.6 Hz), 7.74 (1H, dd, J = 7.6, 1.0 Hz), 6.98 (1H, t, J = 7.6 Hz), 3.90 (3H, s), 1.69 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −13.04 (s) Off-white solid; 79 mg, 57%

 85* J ¹H-NMR (400 MHz, CDCl₃): δ ppm 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.01 (1H, br s), 7.99 (1H, dd, J = 7.8, 1.5 Hz), 6.88 (1H, dd, J = 7.8, 4.4 Hz), 4.06-4.01 (2H, m), 3.94-3.88 (2H, m), 2.31-2.21 (2H, m), 2.05-1.94 (2H, m), 1.72 (3H, d, J = 10.6 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm −9.66 (s) Cream solid; 22 mg, 50%

 86* I ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.19 (1H, d, J = 7.6 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.10 (1H, br s), 6.92 (1H, br s), 1.54 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −10.90 (s) Cream solid; 72 mg, 86%

 87* I ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.91 (1H, s), 7.58 (1H, d, J = 7.6 Hz), 7.55 (1H, d, J = 7.6 Hz), 6.77 (1H, t, J = 7.6 Hz), 1.62 (9H, d, J = 11.1 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −14.42. (s) Yellow solid; 74 mg, 89%

 88 I ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.60- 7.45 (2H, m), 7.05-6.90 (2H, m), 1.69 (9H, d, J = 11.1 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −12.17 (s) Cream solid; 72 mg. 87%

 89 C. ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.70- 7.20 (2H, m), 6.19 (1H, s), 2.04-1.88 (4H, m), 1.61 (3H, d, J = 10.9 Hz), 1.16 (6H, dt, J = 19.2, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 16.12 (s) Brown gum; 17 mg. 31%

 90* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.35 (1H, dd, J = 4.5, 1.5 Hz), 8.09 (1H, dd, J = 7.8, 1.5 Hz), 8.02 (1H, s). 6.94 (1H, dd. J = 7.8, 4.5 Hz), 2.10-1.95 (4H, m), 1.67 (3H, d, J = 10.9 Hz), 1.20 (6H, dt, J = 19.5, 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 16.63 (s) Cream solid; 26 mg, 42%

 91* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.07 (1H, s), 7.69 (1H, dd, J = 7.8, 1.0 Hz), 6.98 (1H, dd, J = 6.8, 1.0 Hz), 6.92 (1H, dd, J = 7.8, 6.8 Hz), 3.07 (3H, s), 2.78 (3H, s), 1.68 (9H, d, J = 11.4 Hz). ³¹P-NMR(162 MHz, DMSO-d6): δ ppm −11.61 (s) White solid; 62 mg, 83%

 92* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.05 (1H, s), 7.67 (1H, dd, J = 6.1, 3.0 Hz), 6.95- 6.88 (2H, m), 3.60 (2H, br s), 3.14 (2H, q, J = 7.1 Hz), 1.66 (9H, d, J = 11.6 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.00 (3H, t, J = 7.1 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.89 (s) White solid; 68 mg, 86%

 93 A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.81 (1H, dd, J = 8.8, 2.5 Hz), 7.64 (1H, d, J = 2.5 Hz), 7.43 (1H, d, J = 8.8 Hz), 4.55 (2H, s), 1.68 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.51 (s) Light brown solid; 24 mg, 32%

 94 G ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.72- 7.60 (2H, m), 7.14-7.09 (2H, m), 3.86 (1.5H, s), 3.79 (1.5H, s), 3.62 (1.5H, s), 1.72 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −10.96 (s) Beige solid; 12 mg, 15%

 95 G ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.48 (1H, d, J = 7.8 Hz), 7.19 (1H, d, J = 2.8 Hz), 6.81 (1H, dd, J = 7.8, 7.1 Hz), 6.71 (1H, dd, J = 7.1, 1.3 Hz), 6.38 (1H, dd, J = 2.8, 1.3 Hz), 3.05 (3H, s), 2.75 (3H, s), 1.65 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.88 (s) White solid; 65 mg, 87%

 96 G ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.50 (1H, br dd, J = 7.3, 1.0 Hz), 7.19 (1H, d, J = 2.5 Hz), 6.81 (1H, dd, J = 7.3, 7.1 Hz), 6.78 (1H, dd, J = 7.1, 1.8 Hz), 6.38 (1H, dd, J = 2.5, 1.5 Hz), 3.33 (3H, br s), 3.19 (3H, br s), 1.65 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.51 (s) Beige solid; 43 mg, 58%

 97* A ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.07 (1H, s), 7.68 (1H, d, J = 7.8 Hz), 7.00-6.90 (2H, m), 3.04 (3H, s), 2.77 (3H, s), 2.10-2.00 (2H, m), 2.10-2.00 (2H, m), 1.95-1.85 (4H, m), 1.61 (3H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 10.04 (s) Dark pink gum; 52 mg, 86%

 98 G ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.66 (1H, d, J = 7.6 Hz), 7.60 (1H, d, J = 7.6 Hz), 7.13-7.05 (2H, m), 3.44 (3H, s), 3.04 (3H, s), 1.70 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.18 (s) Dark purple gummy solid; 25 mg, 34%

 99 C ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.72-7.62 (6H, m), 7.53-6.44 (6H, m), 6.41 (1H, t, J = 2.0 Hz), 2.14 (3H, d, J = 10.1 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm 17.24 (s) White solid, 126 mg, 88%

100* C ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.84-7.76 (2H, m), 7.70-7.63 (4H, m), 7.56-7.44 (6H, m) 2.17 (3H, d, J = 10.4 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm 15.16 (s) Beige solid, 111 mg, 87%

101 K ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.80-7.73 (2H, m), 7.69 (2H, d, J = 2.0 Hz), 7.55-7.47 (3H, m), 6.41 (1H, t, J = 2.0 Hz), 1.87 (6H, d, J = 10.4 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm −0.30 (s) White solid, 75 mg, 69%

102* K ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.84-7.74 (4H, m), 7.58-7.49 (3H, m), 1.89 (6H, d, J = 10.9 Hz). ³¹P-NMR (162 MHz, CDCl₃): δ ppm 1.37 (s) White solid, 93 mg, 86%

103 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.46 (2H, br s), 6.21 (1H, t, J = 1.8 Hz), 2.48-2.38 (3H, m), 1.28 (18H, dd, J = 16.2, 7.1 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 63.15 (s) White solid, 115 mg, 95%

104* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.67 (2H, br s), 2.50-2.43 (3H, m), 1.30 (18H, dd, J = 16.2, 7.1 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 62.53 (s) Brown solid, 101 mg, 97%

105 G ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.67- 7.53 (15H, m), 3.92 (2H, br s), 3.64-3.61 (2H, m), 3.55-3.51 (2H, m). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm 31.60 (s) Grey solid, 80 mg, 89%

106 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.05 (1H, s), 6.99 (1H, s), 3.57 (3H, br s), 3.02 (3H, br s), 1.70 (9H, d, J = 11.4 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −12.68 (s) Brown oil; 33 mg, 90%

107 C ¹H-NMR (400 MHz. DMSO-d6): δ ppm 7.40 (1H, br s), 7.35 (1H, br s), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −11.59 (s) White solid, 55 mg, 96%

108* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.39 (1H, s), 6.16 (1H, d, J = 1.8 Hz), 1.65 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −11.48 (s) White solid, 41 mg, 64%

109* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.05 (1H, s), 2.10 (3H, br s), 1.89 (3H, s), 1.64 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.67 (s) White solid, 75 mg, 93%

110 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 6.65 (2H, s), 2.60 (2H, t, J = 7.6 Hz), 1.71 (2H, sext, J = 7.6 Hz), 1.65 (9H, d, J = 11.6 Hz), 0.90 (3H, t, J = 7.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.54 (s) White solid, 59 mg. 64%

111* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.25 (1H, br s), 5.95 (1H, br s), 2.21 (3H, br s), 1.65 (9H, d, J = 11.4 Hz). ³¹P-NMR(162 MHz, DMSO-d6): δ ppm −10.63 (s) White solid, 105 mg. 96%

112* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.52 (1H. m), 6.57 (1H, d, J = 1.8 Hz), 1.67 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO- d6): δ ppm −11.43 (s) Off-white solid. 85 mg, 66%

 113* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.11 (1H, br s), 6.75 (1H, br s), 1.65 (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.40 (s) White solid, 85 mg, 76%

114* C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.68 (1H, d, J = 0.8 Hz), 7.41 (1H, d, J = 0.8 Hz), 1.67 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm -10.42 (s) Off-white solid, 92 mg, 79%

115* F ¹H-NMR (400 MHz, DMSO-d6): δ ppm 6.38 (1H, br.s), 2.25 (3H, s), 2.06 (3H, s), 1.65 (9H, d, J = 11.7 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.75 (s) Pale brown gum, 124 mg, 100%

116* F ¹H-NMR (400 MHz. DMSO-D6): δ ppm 6.35 (1H, s), 2.55 (2H, q, J = 7.4 Hz). 2.04 (3H, s), 1.61 (9H, d, J = 11.7 Hz), 1.18 (3H, t, J = 7.4 Hz). ³¹P-NMR (162 MHz. DMSO-d6): δ ppm −8.54 (s) Pale brown gum, 127 mg, 100%

117 F ¹H-NMR (400 MHz. DMSO-D6): δ ppm 6.78 (2H, br s), 1.66 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.81 (s) Off-white solid, 117 mg. 95%

118 F ¹H-NMR (400 MHz, DMSO-D6): δ ppm 6.71 (2H, br s), 3.08 (1H, brs), 1.65 (9H, d, J = 11.9 Hz), 1.27 (6H, brs). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −8.08 (s) Pale orange gum, 130 mg, 100%

119 F ¹H-NMR (400 MHz, DMSO-D6): δ ppm 6.77 (2H, br s), 2.66 (2H, q, J = 7.5 Hz), 1.65 (9H, d, J = 11.4 Hz), 1.24 (3H, t, J = 7.5 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −8.65 (s) Pale yellow gum, 119 mg, 98%

120* C ¹H-NMR (400 MHz, DMSO-D6): δ ppm 7.04 (1H, br s), 6.55 (1H, s), 2.11 (3H, s), 1.64 (9H, d, J = 11.9 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.00 (s) Pale yellow gum, 109 mg, 96%

121 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.47 (1H, br s), 7.42 (1H, br s), 1.61 (9H, d, J = 11.5 Hz). ³¹P-NMR (162 MHz. DMSO-d6): δ ppm −10.94 (s) White solid, 122 mg, 93%

122 C ¹H-NMR (400 MHz, DMSO-d6): δ ppm 7.33 (2H, br s), 4.44 (1H, br s), 4.32 (2H, s), 1.64 (9H, d, J = 11.5 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.48 (s) Yellow gum, 101 mg, 87%

123* C 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.12 (1H. br s), 3.79 (3H, br s), 1.68 (9H, d, J = 12.3 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.42 (s) White powder, 91 mg, 69%

124* A 1H-NMR (400 MHz, DMSO-d6): δ ppm 7.73 (0.5H, br s), 7.61 (0.5H, br s) [the signals at 7.73 ppm and 7.61 ppm coalesce to a br s at 7.69 ppm on warming to 75° C.], 3.62 (0.5H br s), 3.43 (0.5H, br s) [the signals at 3.62 ppm and 3.43 ppm coalesce to a br s at 3.61 ppm on warming to 75° C.], 2.24 (4H, br s), 1.96 (1H, m), 1.84 (1H, m), 1.67, (9H, d, J = 11.6 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.75, −10.26 (s) [the two signals at −9.75 ppm and −10.26 ppm coalesce to a singlet at −9.86 ppm on warming to 75° C.]. Pink powder, 109 mg, 83%

125 C 1H-NMR (400 MHz, DMSO-d6): δ ppm 5.64 (1H, s), 2.05 (6H, br s), 1.57, (9H, d, J = 11.2 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.69 (s) White powder, 108 mg, 88%

126* C 1H-NMR (400 MHz, DMSO-d6): 7.30 (1H, br s), 2.25-2.06 (3H, m) (the signals at 2.25- 2.06 ppm coalesce to a br s at 2.15 ppm on warming to 75° C.]. ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −9.37, −10.26, −11.47 (s) [the three signals at −9.37 ppm, −10.26 ppm and −11.47 ppm coalesce to a br s at −10.11 ppm on warming to 75° C.] Grey solid, 49 mg, 94%

127 C 1H-NMR (400 MHz, DMSO-d6): 7.39-7.08 (2H, m), 1.97-1.88 (3H, m), 1.58 (9H, d, J = 11.5 Hz). ³¹P-NMR (162 MHz, DMSO-d6): δ ppm −10.59 (s) *structural assignment to be confirmed: structure may be a regioisomer of this structure in which the Au is connected through a different N atom of the heterocyclic ring, or may represent a mixture of the possible regioisomers. **assigned on basis of X-ray crystallography experiments, although may represent a mixture of the possible regioisomers

Example 2 Growth Media Tryptic Soy Broth

Formula/Litre Pancreatic Digest of Casein 17.0 g  Enzymatic Digest of Soybean 3.0 g Sodium Chloride 5.0 g Di-potassium hydrogen Phosphate 2.5 g Glucose 2.5 g

Directions for use: Dissolve 30 g of the medium in one litre of purified water, mix thoroughly, and then autoclave at 121° C. for 15 minutes.

Luria Broth

Formula/Litre Tryptone 10.0 g  Yeast Extract 5.0 g NaCl 5.0 g

Directions for use: Dissolve components in 1 litre of distilled or deionized water and sterilize by autoclaving at 121° C. for 15 minutes.

Mueller Hinton II Broth (Cation-Adjusted)

Formula/Litre Beef Extract 3.0 g Acid Hydrolysate of Casein 17.5 g  Starch 1.5 g *Adjusted and/or supplemented as required with appropriate salts to provide 20-25 mg/L of calcium and 10-12.5 mg/L of magnesium and as additionally required to meet performance criteria.

Directions for use: Dissolve components in 1 litre of distilled or deionized water and sterilize by autoclaving at 121° C. for 15 minutes.

Brain Heart Infusion Broth

Formula/Litre Brain Heart Infusion solids 12.5 g Beef heart infusion solids 5 g Proteose peptone 10 g Glucose 2 g Sodium Chloride 5 g Di-sodium Phosphate 2.5 g

Directions for use: Dissolve components in 1 litre of purified water. Heat the mixture with frequent agitation to completely dissolve the medium, and sterilize by autoclaving at 121° C. for 15 minutes.

Growth Assay for S. aureus.

Stock solution of the test compounds (20 mg/ml) in dimethyl sulfoxide (DMSO) were serially diluted in DMSO and each diluted compound added in duplicate to a 96-well plate to a final DMSO concentration of 2% (v/v). An overnight culture of S. aureus (Oxford strain) grown in tryptic soy broth (TSB) was diluted to approximately 5×10⁷ cfu/ml and 150 μl of this sample was added to each well of the 96-well plates. Control wells included an ‘untreated’ control with bacteria in TSB in the presence of 2% DMSO and a negative sample (containing 150 μl TSB growth media in the presence of 2% DMSO). Plates were incubated in a shaking incubator at 37° C. for 22-24 hours and bacterial growth assessed by absorbance at a wavelength of 595 nm. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of compound that inhibited growth compared to the no-treatment control.

Variation of growth assays for:

Klebsiella pneumoniae, Acinetobacter baumannnii or E. coli (ATCC 25922): use of 1/100 overnight dilution to set up assay, medium used: Luria broth (LB); incubation without shaking.

P. aeruginosa (ATCC 27853): use of 1/100 overnight dilution to set up assay, medium used: Cation adjusted Mueller Hinton broth (CaMHB); incubation without shaking.

S. aureus K. pneumoniae E. coli P. aeruginosa Com- MIC MIC MIC MIC pound (μg/mL) (μg/mL) (μg/mL) (μg/mL) 1 <0.8 3.1-6.3 3.1 12.5 2 <0.8 6.3 3.1-6.3 12.5 3 <0.8 12.5  12.5    25-50 4 <0.8 3.1 1.6 12.5 5 <0.8 3.1 6.3 12.5 6 <0.8 3.1-6.3 1.6 12.5 7 <0.8 3.1-6.3 6.3   6.3-12.5 8 <0.8 3.1-6.3 6.3 12.5 9 <0.8 6.3 3.1-6.3 12.5 10 ≤0.8 1.6-3.1 1.6-3.1 11 ≤0.8 12.5-25  12.5  12 1.6-3.1 1.6-3.1 13 3.1 1.6-3.1 14 <0.8 3.1 1.6 15 <0.8 3.1-6.3 1.6-3.1 16 0.8 3.1-6.3 3.1-6.3 17 <0.8 3.1-6.3 3.1 18 0.8 3.1 1.6-3.1 19 0.8 3.1-6.3 1.6-3.1 20 <0.8 3.1 1.6 21  0.8-1.6 3.1 1.6 22 1.6 3.1 1.6 23 0.8 1.6-3.1 1.6 24  0.8-1.6 3.1 1.6-3.1 25 <0.8 3.1 0.8-1.6 26  0.8-1.6 3.1 1.6 27 0.8 3.1 1.6 28 <0.8 3.1 0.8-1.6 29  0.8-1.6 3.1 1.6 30 <0.8 3.1 1.6 31 <0.8 3.1 0.8-1.6 32 <0.8 3.1 0.8-1.6 33 <0.8 3.1 1.6 34 1.6 12.5  6.3 12.5-25 35 1 6.3 6.3 12.5 36 <0.8 3.1 3.1-6.3   6.3-12.5 37 0.8 3.1-6.3 1.6 38 <0.8 3.1 3.1   6.3-12.5 39 <0.8 3.1-6.3 6.3 12.5 40 <0.8 3.1-6.3 3.1-6.3 12.5 41 1.6 3.1 1.6-3.1 42 ≤0.8 1.6-3.1 1.6 43 <0.8 3.1 0.8-1.6 44 0.8 3.1 1.6 45 0.8 3.1 1.6 46 <0.8 3.1 0.8-1.6 47 <0.8 3.1 1.6-3.1 48 <0.8 1.6 49 <0.8 1.6-3.1 0.8-1.6 50 <0.8 3.1 1.6 51  0.8-1.6 3.1 0.8-1.6 52 <0.8 3.1 1.6 53 <0.8 3.1 1.6 54 <0.8 3.1 1.6 55 <0.8 3.1 1.6 56 <0.8 3.1-6.3 1.6-3.1 57 <0.8 3.1 1.6-3.1 58 <0.8 3.1 1.6 59 <0.8 3.1 1.6 60 <0.8 3.1-6.3 3.1 61 <0.8 3.1-6.3 3.1 62 <0.8 3.1 1.6 63 <0.8 1.6-3.1 1.6 64 <0.8 3.1 1.6 65 <0.8 3.1 1.6 66 <0.8 3.1 <0.8  67 <0.8 3.1 1.6 68 <0.8 3.1 1.6 69 <0.8 3.1 1.6 70 <0.8 3.1-6.3 1.6 71 ≤0.8 1.6-3.1 3.1 25 72 ≤0.8 1.6 3.1-6.3 12.5-25 73 ≤0.8 1.6-3.1 3.1-6.3   25-50 74 ≤0.8 1.6 3.1 25 75 ≤0.8-1.6 ≤0.8-3.1  1.6-3.1 25 76 ≤0.8-1.6 1.6-25  3.1-25  12.5-25 77 ≤0.8 ≤0.8-1.6  1.6-3.1 12.5 78 ≤0.8-1.6 ≤0.8-3.1  1.6-3.1 25 79  ≤0.8-12.5 ≤0.8-1.6  1.6 25 80  ≤0.8-12.5 ≤0.8-1.6  1.6 25 81 ≤0.8 1.6 1.6-3.1 12.5 82 ≤0.8 1.6-3.1 3.1 12.5 83 ≤0.8-1.6 1.6-3.1 3.1 12.5-25 84 ≤0.8 ≤0.8-3.1  1.6-3.1 12.5 85  1.6-3.1 1.6-6.3  6.3-12.5   25-50 86 ≤0.8-3.1 ≤0.8-3.1  3.1  6.3-25 87 ≤0.8-3.1 ≤0.8-3.1  3.1-6.3 12.5-25 88 ≤0.8-3.1 ≤0.8-3.1  1.6-3.1   6.3-12.5 89 ≤0.8 3.1-6.3 6.3 12.5 90 ≤0.8 3.1 6.3 12.5-25 91 ≤0.8-1.6 ≤0.8-1.6  3.1 12.5 92 ≤0.8-1.6 1.6 3.1-6.3   6.3-12.5 93 ≤0.8 0.8 <0.8-3.1   6.3-25 95  1.6-3.1 1.6-3.1 3.1-6.3   6.3-12.5 96 ≤0.8-3.1 1.6-3.1 3.1-6.3   3.1-12.5 97  1.6-3.1 3.1 6.3 12.5 98 ≤0.8-1.6 1.6-3.1 3.1   3.1-12.5 99 1.6 25-50  50-100 >100 100  1.6-3.1 37.5-50  100    >100 101 ≤0.8-1.6 12.5-25  12.5-50  25 102 ≤0.8-1.6 12.5-25  12.5-25  25 103 ≤0.8-1.6 25-50 25-75 25 104 ≤0.8-1.6 25-50 50-75 50 105  1.6-3.1 >100     100    100 106 ≤0.8-3.1 1.6-3.1 3.1 12.5-25 107 ≤0.8-1.6 3.1-6.3 3.1-6.3 12.5 108 ≤0.8-1.6 3.1 3.1-6.3 12.5 109 0.8 3.1-6.2 1.6-3.1 25 110 0.8 1.6-6.2 1.6-3.1 12.5-25 111  0.4-0.8 3.1 1.6-3.1 12.5-25 112  0.4-1.6 1.6-3.1 1.6-3.1 25 113  0.8-1.6 1.6-6.2 1.6-3.1 25 114 ≤0.2-0.8 1.6-3.1 1.6-3.1 25 115  0.4-0.8 3.1 1.6-3.1 12.5-25 116  0.8-1.6 3.1 3.1 12.5-25 117 0.8 3.1 1.6-3.1 25 118  0.4-0.8 3.1 1.6-3.1 25 119  0.4-0.8 3.1 1.6-3.1 25 120 0.8 3.1 3.1 25 Inhibition of Neisseria gonorrhoeae (NCTC 8375) Growth on Solid Media

N. gonorrhoeae was grown for 48 hours at 37° C. on Chocolate agar plates (BD Diagnostics). A culture loop-full of bacterial culture was picked from the plate and re-suspended in 50 μl sterile phosphate buffered saline. The suspension was spread evenly onto the surface of a fresh chocolate agar plate and left to dry (approximately 5 minutes). Small discs of blotting paper were placed on the surface of the agar plate and 3 μl of test compounds (at 20 mg/ml) were applied to the discs. The plates were incubated overnight at 37° C. and zones of clearance around the disc were measured.

HepG2 Cell Inhibition Assay

Cell counting kit-8 (Sigma, CCK-8) assays were performed to assess the effect of compounds on cell viability. The assay is based on the reduction of a water-soluble tetrazolium salt (WST-8) by cellular dehydrogenases to a formazan dye which can be detected spectroscopically. 96-well plates were seeded with the human hepatocyte cell line (HepG2) at approximately 8×10³ cells per well in Eagle's Minimum Essential Medium (EMEM) with Earle's salts and sodium bicarbonate supplemented with 10% heat-inactivated foetal bovine serum 2 mM glutamine and 1% non-essential amino acids (NEAA). The following day serial dilutions of compounds (dissolved and diluted in DMSO) were added to the cells in duplicates. Control wells included an ‘untreated’ control where cells were grown in the presence of 1% DMSO and a ‘medium only’ control (plus 1% DMSO). After 24 hours CCK-8 reagent (10 μl) was added to each well and cell viability was assessed by measuring the absorbance at a wavelength of 450 nm after 2-3 h hours. Only living cells can reduce the tetrazolium salts into coloured formazan products. Results were expressed as 50% growth inhibition (TD₅₀) values compared to ‘untreated’ control.

HepG2 cell Compound TD₅₀ (μg/mL) 1 4 2 3 3 6 4 7 5 6 6 9 7 11 8 9 9 7 10 15 11 4 12 4 13 3 14 7 15 3 16 10 17 8 18 5 19 13 20 2 21 4 24 5 25 5 26 6 27 4 28 9 29 3 30 3 31 3 36 7.3 37 11.9 38 7 39 9 40 6 41 16 42 5 43 4 44 5 45 5 46 5 47 3.9 48 4 50 3 51 3 Efficacy Studies in the Galleria mellonella Model

G. mellonella larvae at 5^(th) or 6^(th) instar stage were purchased from a commercial supplier and used within 3 days. Prior to infection larvae were kept at room temperature. Larvae were infected with bacteria (various Gram positive and negative bacteria, including S. aureus, K. pneumoniae, E. coli and P. aeruginosa) using a sterile Hamilton syringe. Bacteria cultures were grown overnight, washed ×3 in PBS and resuspended in PBS. Larvae were wiped with 70% ethanol and 10 μl of bacteria solution (to cause 80%-100% death within 3-4 days) was injected into the bottom right proleg of the larvae. Larvae injected with 10 μl of PBS were used as negative controls. Larvae were then placed in petri dishes (1 dish per condition) containing filter paper at the bottom of the dish at 37° C. After various time points post infection (1-6 h), larvae were taken from the incubator wiped again with 70% ethanol and injected with 10 μl of various concentrations of compound, dissolved in either 5% dimethyl sulfoxide, 5% ethanol or 5% 1-methyl-2-pyrrolidinone into a proleg on the left hand-side. Control larvae received 10 μl of 5% solvent. Ten larvae were injected for each condition. To assess the toxicity of the compound, larvae were injected with various concentrations of compound alone. Larvae were returned to a 37° C. incubator and checked daily. Larvae were considered dead when no movement occurred when touched with a blunt pair of forceps. Black or discoloured larvae which still showed movement were considered to be alive. Numbers of dead larvae were recorded each day.

Primary Cells Viability Assay

Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from venous blood obtained from healthy volunteers as previously described (Nauseef, Methods in Molecular Biology, 412 (2007), pp. 15-20). In brief, heparinised blood was diluted 1:1 with 3% Dextran-500 PBS solution (Sigma) to allow for erythrocyte sedimentation. Buffy coat was centrifuged over Hypaque-Ficoll (GE Lifescience) and PBMCs were carefully collected from the interface of the Hypaque-Ficoll and the upper liquid layer. Pelleted neutrophils were collected after hypotonic lysis of residing erythrocytes. Isolated cells were washed and suspended in culture media (RPMI+10% FBS) at 2×106 cells/mL. Cell suspensions were transferred into 96-well plates containing compound in serially diluted (1% final volume). After 24 hours, the reaction was stopped and cells were stained with AnnexinV and 7-AAD. Results were determined by FACSCalibur and viability was defined for AnnexinV/7-AAD double negative cells population.

Biofilm Prevention Assay (S. aureus)

The effect of a test compound on the formation of a S. aureus biofilm was assessed using a biofilm prevention assay as described by Merritt et al. Current Protocols in Microbiology, 2011, 1B.1.1-1B1.18 with slight modifications. Briefly, S. aureus was grown overnight in tryptic soy broth (TSB) and diluted to 1/100 before 150 μL was added to the wells of a flat bottomed 96-well plate. Three microliters of compound at the appropriate dilution in DMSO was added to the wells in duplicate. Controls included a positive control with bacteria alone in TSB with 2% DMSO and a negative (no bacteria) control with 150 μL TSB containing 2% DMSO. Plates were sealed with AeraSeal™ and incubated at 37° C. for 24 hours. Plates were then washed three times with PBS, dried at 60° C. for 1 hour and stained with crystal violet for 1 hour. The plates were again washed three times with water, then dried 33% acetic acid was added to re-solubilize the crystal violet stain bound to the adherent cells. Absorbance was then measured at 595 nm and expressed as a percentage of the bacteria only control. A biofilm inhibitory concentration (BIC₉₀) was determined as the concentration at which biofilm mass (measured by crystal violet staining) was reduced by at least 90% compared to untreated controls.

The effect of a test compound on preformed S. aureus biofilms can also be assessed. Briefly S. aureus was plated in 96-well plates as described in above and incubated at 37° C. for 24 hours. Biofilms were then washed 3 times with TSB and 150 μL of fresh TSB and 3 μL of compound at the appropriate dilution in DMSO was added to the wells in duplicate. Plates were again sealed with AeraSeal™ and reincubated at 37° C. for 24 hours. Biofilm was then detected as described above.

S. aureus BF dispersal Compound BIC₉₀ (μg/mL) 1 ≤0.8 3 ≤0.8 12 ≤0.8 14 ≤0.8 18 ≤0.8 21 1.6 25 ≤0.8 28 ≤0.8 32 ≤0.8 36 ≤0.8 42 ≤0.8 43 ≤0.8 46 ≤0.8 48 ≤0.8 49 ≤0.8 54 ≤0.8 57 ≤0.8 Biofilm Assay for A. baumannii

A. baumannii was grown overnight in LB broth and diluted 1/00-1/500 before 200 μL was added to the wells of a flat bottomed 96-well plate with TSP 96 pins lid inserted. Plates with pins were incubated at 37° C. for 24 hours. Pins were washed with sterile phosphate buffered saline three times and exposed to compounds at pre-determined concentration in LB broth for 24 hours. Pins were washed again and either stained with crystal violet as described in the S. aureus biofilm assay, or incubated with LB media for 24 hours and the minimum biofilm eradication concentration (MBEC) was measured as the lowest concentration of compounds preventing further planktonic growth.

Compound Minimum biofilm eradication conc. (MBEC) μg/mL 1 2.5-5  3  5-10 42 10-20 36 20 52 10 53 10 57 10 58 20 59 20 60 10 61 10 62 10 63 20 66 20 70 10 105 40 84 10

Persister Cell Assay

To determine whether S. aureus persister cells were susceptible to treatment with a test compound, a persister cell (or SCV) isolate hemB mutant of NCTC 8325-4 was used (Von Eiff et al., (1997) J Bacteriol 179:4706-4712). This persister cell variant displays varying resistance to erythromycin and the aminoglycosides gentamicin and kanamycin. Growth assays were performed essentially as described above with the bacteria being grown in TSB. Disc assays were also performed by plating bacteria on TSB agar. Discs impregnated with an amount of test compound were placed on top of the agar. The plates were incubated overnight at 37° C. and any zone of bacterial inhibition was observed.

Sensitivity of Multidrug Resistant Clinical Isolates

The activity of test compounds against multi-drug resistant bacterial strains was assessed by the disk diffusion assay; a standardised method to assess for the antimicrobial susceptibility of microorganisms (adapted from EUCAST, Version 5, January 2015). In brief, bacterial cultures were suspended in phosphate buffer and spread evenly onto blood agar plates. Cellulose disks (5 mm) were placed onto the agar plates and 3 μl test compound (60 μg/disk) were pipetted to the centre. A panel of standard antibiotics disks (Sigma) were used to control for the antimicrobial resistance profile of the individual strains (quantity as indicated in the table). The plates were then placed into a thermo-incubator and were cultured at 37° C. over-night. Activity was recorded by measuring the zone of clearance (mm) around the disks.

Size of clearance Size of clearance CDC Threat zone (mm) for 60 μg zone (mm) for 60 μg Clinical isolate classification level of Compound 35 of Compound 36 E. faecalis VRE Serious 12 20 DSM13591 A. baumannii MDRA Serious 7 11 NC13421 K. pneumoniae ESBL Serious 8 15 13368 E. coli 13400 ESBL Serious 11 ND

Comparative Data—Size of Clearance of Zone (mm)

Compund quantity E. faecalis A. baumannii K. pneumoniae E. coli Antibiotic (μg) DSM13591 NC13421 13368 13400 Amoxycillin 2 17 R R R Azetronam 30 R R 11 23 Cefotaxime 30 R R R 18 Ceftriaxone 30 R R R R Colistin 10 N/A 11   9.5 12 Ertapenem 10 14 R R 30 Imipenem 10 26 R 18 29 Linezolid 10 22 N/A N/A N/A Meropenem 10 17 R 22 ND Piperacillin/Tazo 36 21 R 15 17 bactam Vancomycin 30 R N/A N/A N/A R = resistant N/A = strain not sensitive ND = not done

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1. A method of preventing or treating a bacterial infection by administering a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof:

wherein: P^(X) is selected from the group consisting of (P1), (P2) and (P3);

wherein R^(P1) and R^(P2) are each independently selected from methyl, ethyl, isopropyl and phenyl; R^(P3) is selected from the group consisting of methyl and ethyl, isopropyl, t-butyl, cyclopentyl, phenyl, 4-membered or 5-membered heterocycloalkyl group linked to phosphorus via a carbon atom in the ring, including a single heteroatom independently selected from NR^(Z), O and S, —CF₃, —CH₂CF₃, —CH₂CF₂H, —CH₂CH₂OR^(PB), —CH₂Q and —(CH₂)₂Q; wherein Q is a C₅₋₆ heteroaryl group, optionally substituted with one or more groups R^(PA); R^(P4) is selected from methyl and ethyl; m is an integer selected from 1, 2 or 3; R^(M) is one or more optional substituents on the ring independently selected from R^(PC) when attached to a carbon atom adjacent the phosphorus atom, or —OH, —OC₁₋₃alkyl and R^(PC), when attached to other ring carbons; -L^(B)- is methylene, ethylene or is absent; when -L^(B)- is present, R^(P4) is absent and R¹ is selected from N, CH and CR^(PC); when -L^(B)- is absent, R¹ is selected from the group consisting of O, NR^(Z), SO₂, CH₂, CHF, CF₂ and CHR^(P)C; wherein R^(Z) is selected from the group consisting of H, C₁₋₃alkyl, COC₁₋₃alkyl and SO₂C₁₋₃alkyl; R⁵ and R⁸ are each independently selected from H and R^(PC); R⁶ and R⁷ are each independently selected from H and R^(PC); wherein R^(PC) is selected from the group consisting of C₁₋₃alkyl, optionally substituted with one or more groups R^(PD); wherein R^(PA) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AL), —F, —Cl, —Br, —CN —OH, —OR^(PE), —CF₃, —CF₂H, —COR^(PE), —CH₂OH, —CH₂OR^(PE), —COOH, —COOR^(PE), —CONH₂, —CONHR^(PE), —CONR^(PE) ₂, —OCOR^(PE), —OCONH₂, —OCONHR^(PE), —OCONR^(PE) ₂, —NH₂, —NHR^(PE), —NR^(PE) ₂, —SO₂NH₂, —SO₂NHR^(PE) ₂, —SO₂NR^(PE) ₂, —SO₂R^(PE), —NHCOH, —NHCOR^(PE), —NR^(PE)COH and —NR^(PE)COR^(PE); and R^(PB) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AT), C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or C₅₋₆heterocycloalkenyl optionally substituted with one or more groups R^(AT), phenyl optionally substituted with one or more groups R^(AR), and C₅₋₆heteroaryl optionally substituted with one or more groups R^(AR); R^(PE) is selected from linear or branched C₁₋₄alkyl optionally substituted with one or more groups R^(PD); and R^(PD) is selected from the group consisting of F, OH and OC₁₋₃alkyl; R^(A) is selected from the group consisting of H; linear or branched C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl and C₅₋₆heterocycloalkenyl optionally substituted with one or more groups R^(AL), C₅₋₆heteroaryl, optionally substituted with one or more groups R^(A1), C₁₋₃alkyl substituted by phenyl or C₅₋₆heteroaryl, which groups may optionally substituted with one or more groups R^(A1), R^(B) is selected from —COR^(A2) and —SO₂R^(A2); or R^(A) and R^(B) together with the nitrogen atom to which they are attached form a 5- or 6-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from oxo, ═NH; phenyl optionally substituted with one or more groups R^(A1), R^(A2), and R^(A1); an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from oxo, —NO₂; C(═O)N(R^(N1))₂, wherein each R^(N1) is independently selected from R^(N2) and —OR^(N3), wherein R^(N2) and R^(N3) are each independently selected from linear unsubstituted C₁₋₆alkyl; phenyl optionally substituted with one or more groups R^(A1), R^(A2) and R^(A1); with the proviso that when P^(X) is P(C₂H₅)₃, —NR^(A)R^(B) is not selected from the groups (X1) or (X6)

with the further proviso that when P^(X) is PPh₃, —NR^(A)R^(B) is not selected from the groups (X15):

wherein R^(A1) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AL), —F, —Cl, —Br, —CN —OH, —OR^(A2), —CF₃, —CF₂H, —COR^(A2), —CH₂OH, —CH₂OR^(A2), —CHR^(A2)OH, CHR^(A2)OR^(A2) —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂, —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂, —NH₂, —NHR^(A2), —NR^(A2) ₂, —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂, —SO₂R^(A2), —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2); R^(A2) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AT), C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or C₅₋₆heterocycloalkenyl optionally substituted with one or more groups R^(AT), phenyl optionally substituted with one or more groups R^(AR), and C₅₋₁₀heteroaryl optionally substituted with one or more groups R^(AR); where N is substituted by 2 R^(A2) groups, the N and the R^(A2) groups may together form a N-containing C₅₋₆ heterocycloalkyl group; R^(AL) is selected from the group consisting of linear or branched C₁₋₆alkyl optionally substituted with one or more groups R^(AT); —F, —CN —OH, —OR^(A2), —CF₃, —CF₂H, —COR^(A2), —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂, —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂, —NH₂, —NHR^(A2), —NR^(A2) ₂, —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂, —SO₂R^(A2), —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2); and wherein R^(AR) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AL), —F, —Cl, —Br, —CN —OH, —OR^(1A1), —CF₃, —CF₂H, —COR^(1A1), —CH₂OH, —CH₂OR^(1A1), —CHR^(1A1)OH, CHR^(1A1)OR^(1A1) —COOH, —COOR^(1A1), —CONH₂, —CONHR^(1A1), —CONR^(1A1) ₂, —OCOR^(1A1), —OCONH₂, —OCONHR^(1A1), —OCONR^(1A1) ₂, —NH₂, —NHR^(1A1), —NR^(1A1) ₂, —SO₂NH₂, —SO₂NHR^(1A1) ₂, —SO₂NR^(1A1) ₂, —SO₂R^(1A1), —NHCOH, —NHCOR^(1A1), —NR^(1A1)COH and —NR^(1A1)COR^(1A1); R^(AT) is selected from the group consisting of —F, —CN —OH, —OC₁₋₃alkyl, —CF₃, —CF₂H, —COC₁₋₃alkyl, —COOH, —COOC₁₋₃alkyl, —CONH₂, —CONHC₁₋₃alkyl, —CON(C₁₋₃alkyl)₂, —OCOC₁₋₃alkyl, —OCONH₂, —OCONHC₁₋₃alkyl, —OCON(C₁₋₃alkyl)₂, —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)₂, —SO₂NH₂, —SO₂NH(C₁₋₃alkyl)₂, —SO₂N(C₁₋₃alkyl)₂, —SO₂(C₁₋₃alkyl), —NHCOH, —NHCO(C₁₋₃alkyl), —N(C₁₋₃alkyl)COH and —N(C₁₋₃alkyl)CO(C₁₋₃alkyl).
 2. The method according to claim 1, wherein P^(X) is P1, and either (a) both R^(P1) and R^(P2) are methyl; or (b) both R^(P1) and R^(P2) are ethyl; or (c) R^(P1) is methyl and R^(P2) is ethyl. 3-4. (canceled)
 5. The method according to claim 2, wherein R^(P3) is selected from the group consisting of methyl, ethyl, oxetanyl, tetrahydrofuranyl, —CF₃, —CH₂CF₃, —CH₂CF₂H, —CH₂OCH R^(PB), where R^(PB) is a linear or branched C₁₋₆ alkyl; and —CH₂Q. 6-12. (canceled)
 13. The method according to claim 1, wherein P^(X) is P2, and the ring in P2 is not substituted. 14-16. (canceled)
 17. The method according to claim 1, wherein P^(X) is P3, -L^(B)- is methylene or ethylene and either R¹ is N; or R¹ is CH; or R¹ is CR^(PC), wherein R^(PC) is unsubstituted C₁₋₃ alkyl. 18-24. (canceled)
 25. The method according to claim 1, wherein P^(X) is selected from the group consisting of:


26. The method according to claim 1, wherein R^(A) is linear or branched C₁₋₆alkyl optionally substituted with one or more groups R^(AL); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2). 27-30. (canceled)
 31. The method according to claim 1, wherein R^(A) is C₅₋₆heteroaryl, optionally substituted with one or more groups R^(A1); and R^(B) is selected from —COR^(A2) and —SO₂R^(A2). 32-38. (canceled)
 39. The method according to claim 1, wherein —NR^(A)R^(B) is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from: oxo; phenyl optionally substituted with one or more groups R^(A1); R^(A2), and R^(A1). 40-50. (canceled)
 51. The method according to claim 1, wherein —NR^(A)R^(B) is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from: phenyl optionally substituted with one or more groups R^(A1); R^(A2), and R^(A1).
 52. The method according to claim 51, wherein the 5- or 6-membered heteroaryl group contains up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of —NR^(A)R^(B). 53-58. (canceled)
 59. The method according to claim 1, wherein NR^(A)R^(B) is an imidazolyl group, bearing a C substituent which is the group (B1)

wherein R^(B1) is selected from the group consisting of —H, —COR^(A2), —CONR^(A2), CO₂R^(A2), and —SO₂R^(A2); R^(B2) is selected from —H, and linear or branched C₁₋₄alkyl; and R^(B3) is selected from the group consisting of —OH, —OR^(A2), —NH₂, —NHR^(A2) and —NR^(A2) ₂.
 60. The method according to claim 1, wherein —NR^(A)R^(B) is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from: oxo; phenyl optionally substituted with one or more groups R^(A1); R^(A2) and R^(A1).
 61. The method according to claim 60, wherein the 8- to 10-membered heterobicyclyl group is a 9-membered heterobicyclyl group. 62-64. (canceled)
 65. The method according to claim 1, wherein —NR^(A)R^(B) is selected from

66-67. (canceled)
 68. The method according to claim 1, wherein the bacterial infection prevented and/or treated is infection by one or more Gram-positive bacteria; or wherein the bacterial infection prevented and/or treated is infection by one or more Gram-negative bacteria.
 69. (canceled)
 70. A method for (a) reducing the biomass of a bacterial biofilm; (b) promoting the dispersal of microorganisms from a bacterial biofilm; (c) killing a microorganism within a bacterial biofilm: (d) sensitizing a microorganism in a bacterial biofilm to an antimicrobial agent; or (e) inhibiting the formation of a bacterial biofilm, the method comprising exposing the bacterial biofilm to an effective amount of a compound as described in claim 1; optionally wherein the bacteria are Gram positive bacteria; or optionally wherein the bacteria are Staphylococcus spp; or optionally wherein the bacteria are multi-drug resistant bacteria; or optionally wherein the bacteria are small colony variants. 71-86. (canceled)
 87. The method according to claim 70, comprising further administering at least one additional antimicrobial agent.
 88. (canceled)
 89. A compound of formula (I):

and pharmaceutically acceptable salts and solvates thereof wherein: P^(X) is selected from the group consisting of (P1), (P2) and (P3);

wherein R^(P1) and R^(P2) are each independently selected from methyl, ethyl, isopropyl and phenyl; R^(P3) is selected from the group consisting of methyl and ethyl, isopropyl, t-butyl, cyclopentyl, phenyl, 4-membered or 5-membered heterocycloalkyl group linked to phosphorus via a carbon atom in the ring, including a single heteroatom independently selected from NR^(Z), O and S, —CF₃, —CH₂CF₃—CH₂CF₂H, —CH₂CH₂OR^(PB), —CH₂Q and —(CH_(Z))Q; wherein Q is a C₅₋₆ heteroaryl group, optionally substituted with one or more groups R^(PA); R^(P4) is selected from methyl and ethyl; m is an integer selected from 1, 2 or 3; R^(M) is one or more optional substituents on the ring independently selected from R^(PC) when attached to a carbon atom adjacent the phosphorus atom, or —OH, —OC₁₋₃alkyl and R^(PC), when attached to other ring carbons; -L^(B)- is methylene, ethylene or is absent; when -L^(B)- is present, R^(P4) is absent and R¹ is selected from N, CH and CR^(PC); when -L^(B)- is absent, R¹ is selected from the group consisting of O, NR^(Z), SO₂, CH₂, CHF, CF₂ and CHR^(PC); wherein R^(Z) is selected from the group consisting of H, C₁₋₃alkyl, COC₁₋₃alkyl and SOC₁₋₃alkyl; R⁵ and R⁸ are each independently selected from H and R^(PC); R⁶ and R⁷ are each independently selected from H and R^(PC); wherein R^(PC) is selected from the group consisting of C₁₋₃alkyl optionally substituted with one or more groups R^(PD); wherein R^(PA) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₁₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AL), —F, —Cl, —Br, —CN —OH, —OR^(PE), —CF₃—CF₂H, —COR^(PE), —CH₂OH, —CH₂OR^(PE), —COOH, —COOR^(PE), —CONH₂, —CONHR^(PE), —CONR^(PE) ₂, —OCOR^(PE), —OCONH₂, —OCONHR^(PE), —OCONR^(PE) ₂, —NH₂, —NHR^(PE), —NR^(PE) ₂, —SO₂NH₂, —SO₂NHR^(PE) ₂, —SO₂NR^(PE) ₂, —SO₂R^(PE), —NHCOH, —NHCOR^(PE), —NR^(PE)COH and —NR^(PE)COR^(PE); and R^(PB) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AT), C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl or C₅₋₆heterocycloalkenyl optionally substituted with one or more groups R^(AT), phenyl optionally substituted with one or more groups R^(AR), and C₅₋₆heteroaryl optionally substituted with one or more groups R^(AR); R^(PE) is selected from linear or branched C₁₋₄alkyl optionally substituted with one or more groups R^(PD); and R^(PD) is selected from the group consisting of F, OH and OC₁₋₃alkyl; R^(A) is selected from the group consisting of H; linear or branched C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, C₅₋₆cycloalkenyl and C₅₋₆heterocycloalkenyl optionally substituted with one or more groups R^(AL), C₅₋₆heteroaryl, optionally substituted with one or more groups R^(A1), C₁₋₃alkyl substituted by phenyl or C₅₋₆heteroaryl, which groups may optionally substituted with one or more groups R^(A1), R^(B) is selected from —COR^(A2) and —SOR^(A2); or R^(A) and R^(B) together with the nitrogen atom to which they are attached form a 5- or 6-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from oxo, ═NH; phenyl optionally substituted with one or more groups R^(A1), R^(A2), and R^(A1); an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from oxo, —NO₂; —C(═O)N(R^(N1))₂, wherein each R^(N1) is independently selected from R^(N2) and —OR^(N3), wherein R^(N2) and R^(N3) are each independently selected from linear unsubstituted C₁₋₆alkyl; phenyl optionally substituted with one or more groups R^(A1), R^(A2) and R^(A1); with the proviso that when P^(X) is P(C₂H₅)₃, —NR^(A)R^(B) is not selected from the groups (X1) or (X6)

with the further proviso that when P^(X) is PPh₃, —NR^(A)R^(B) is not selected from the groups (X15):

(X15) wherein R^(A1) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AL), —F, —Cl, —Br, —CN —OH, —OR^(A2), —CF₃—CF₂H, —COR^(A2), —CH₂OH, —CH₂OR^(A2), —CHR^(A2)OH, CHR^(A2)OR^(A2) —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂, —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂, —NH₂, —NHR², —NR^(A2) ₂, —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂, —SO₂R^(A2), —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2); R^(A2) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AT), C₃₋₆cycloalkyl C₄₋₆heterocycloalkyl C₅₋₆cycloalkenyl or C₅₋₆heterocycloalkenyl optionally substituted with one or more groups R^(AT), phenyl optionally substituted with one or more groups R^(AR), and C₅₋₁₀heteroaryl optionally substituted with one or more groups R^(AR); where N is substituted by 2 R^(A2) groups, the N and the R^(A2) groups may together form a N-containing C₅₋₆ heterocycloalkyl group; R^(AL) is selected from the group consisting of linear or branched C₁₋₆alkyl optionally substituted with one or more groups R^(AT); —F, —CN —OH, —OR^(A2), —CF₃, —CF₂H, —COR^(A2), —COOH, —COOR^(A2), —CONH₂, —CONHR^(A2), —CONR^(A2) ₂, —OCOR^(A2), —OCONH₂, —OCONHR^(A2), —OCONR^(A2) ₂, —NH₂, —NHR^(A2), —NR^(A2) ₂, —SO₂NH₂, —SO₂NHR^(A2) ₂, —SO₂NR^(A2) ₂, —SO₂R^(A2), —NHCOH, —NHCOR^(A2), —NR^(A2)COH and —NR^(A2)COR^(A2); and wherein R^(AR) is selected from the group consisting of linear or branched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl optionally substituted with one or more groups R^(AL), —F, —Cl, —Br, —CN —OH, —OR^(1A1), —CF₃, —CF₂H, —COR^(1A1), —CH₂OH, —CHOR^(1A1), —CHR^(1A1)OH, CHR^(1A1)OR^(1A1) —COOH, —COOR^(1A1), —CONH₂, —CONHR^(1A1), —CONR^(1A1) ₂, —OCOR^(1A1), —OCONH₂, —OCONHR^(1A1), —OCONR^(1A1) ₂, —NH₂, —NHR^(1A1), —NR^(1A1) ₂, —SO₂NH₂, —SO₂NHR^(1A1) ₂, —SO₂NR^(1A1) ₂, —SO₂R^(1A1), —NHCOH, —NHCOR^(1A1), —NR^(1A1)COH and —NR^(1A1)COR^(1A1); R^(AT) is selected from the group consisting of —F, —CN —OH, —OC₁₋₃alkyl, —CF₃, —CF₂H, —COC₁₋₃alkyl, —COOH, —COOC₁₋₃alkyl, —CONH₂, —CONHC₁₋₃alkyl, —CON(C₁₋₃alkyl)₂, —OCOC₁₋₃alkyl, —OCONH₂, —OCONHC₁₋₃alkyl, —OCON(C₁₋₃alkyl)₂, —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)₂, —SO₂NH₂, —SO₂NH(C₁₋₃alkyl)₂, —SO₂N(C₁₋₃alkyl)₂, —SO₂(C₁₋₃alkyl), —NHCOH, —NHCO(C₁₋₃alkyl), —N(C₁₋₃alkyl)COH and —N(C₁₋₃alkyl)CO(C₁₋₃alkyl); with the provisos that when P^(X) is P(CH₃)₃, —NR^(A)R^(B) is not selected from any of the groups (X1) to (X5), (X7) and (X12) to (X15); and when P^(X) is P(C₂H₅)₃, —NR^(A)R^(B) is not selected from the groups (X1), (X6) to (X11), (X13) and (X14); and when P^(X) is PPh₃, —NR^(A)R^(B) is not selected from the groups (X2), (X12), (X14) and (X15):


90. A pharmaceutical composition comprising a compound according to claim 89 and a pharmaceutical acceptable diluent or excipient. 91-94. (canceled) 